PATENT METHODS OF TREATING AGE-RELATED AND INHERITED RETINAL DYSFUNCTIONS RELATED APPLICATION [0001] This application claims priority from U.S. Provisional Application No.63/375,974, filed September 16, 2022, the subject matter of which is incorporated herein by reference in its entirety. GOVERNMENT FUNDING [0002] This invention was made with government support under EY031566, EY022938, and EY027283 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND [0003] Loss of physiological resilience to stress represents a common point of convergence across various age-related degenerative disorders of distinct etiologies. While somatic maintenance processes function with high efficiency in youthful age, such as in the effective repair and/or recycling of misfolded or aggregated protein adducts induced by stress, reduced efficiency of these processes in advanced age can result in aberrant accumulation of toxic aggregates, plaques, and other damage, which compromise cellular and organismal viability in the face of constant exposure to environmental stressors that eventually exceed the dynamic range of recovery by protective mechanisms. Age-related macular degeneration (AMD) is a leading cause of progressive, irreversible blindness in individuals aged over 50 years, with an estimated 11 million individuals afflicted in the United States and approximately 170 million cases worldwide. Clinically, AMD susceptibility has been linked to cigarette smoking and obesity, both of which are known to induce cellular stress and inflammation, in part through epigenetic modifications. Another age-related retinal degeneration of interest is diabetic retinopathy, the leading cause of visual impairment and blindness in the diabetic population, the pathophysiology of which has similarly been associated with inflammatory and oxidative stress. Lastly, with respect to inherited retinal degenerations, such as retinitis pigmentosa, disease susceptibility and progression have been linked to increased proteomic stress, resulting from genetic mutations that accelerate the accumulation of misfolded or mislocalized protein aggregates. [0004] Recent clinical trials aimed at developing treatments for AMD have primarily focused on singular disease pathways. These include visual cycle modulators, complement inhibitors, and growth receptor inhibitors, none of which have achieved desirable results or received FDA approval. The most prevalent form of AMD, in earlier stages of pathogenesis (“dry” AMD), represents approximately 80-90% of the total number of cases, yet no treatments have been approved for dry AMD to date. Likewise, for retinitis pigmentosa and diabetic retinopathy, safe and efficacious therapies are urgently needed. SUMMARY [0005] Embodiments described herein relate to compositions that include stress resilience-enhancing drugs (SREDs) and their use in treating and/or preventing acute and/or chronic forms retinal dysfunction including, for example, age-related or inherited retinal dysfunction and/or age-related or inherited visual impairment and, particularly, acute and/or chronic retinal degenerative diseases, such as age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, and glaucoma. We conducted integrative transcriptomic, proteomic, and phosphoproteomic analyses to identify conserved molecular mechanisms in various models of age-related and inherited retinal degeneration, characterized by impaired resilience to stress. Through selective, targeted pharmacological inhibition of cyclic nucleotide phosphodiesterases, which serve as critical regulatory nodes that modulate intracellular second messenger signaling pathways, the SREDS described herein stabilized the transcriptome, proteome, and phosphoproteome and enhanced resilience to acute and chronic forms of stress in the degenerating retina, thereby preserving tissue structure and function across the various animal models of age-related and inherited retinal diseases. [0006] Accordingly, a method of treating and/or preventing retinal dysfunction in a subject in need thereof can include administering to the subject a therapeutically effective amount of an SRED that can enhance physiological resilience to stress by promoting intrinsic mechanisms of somatic maintenance (e.g., Glul, RdCVF, CREB) and attenuating degenerative processes (e.g., Fas, TNF, HDAC11, C3) that drive retinal degeneration and associated pathology and treat and/or prevent the retinal dysfunction in the subject. [0007] In some embodiments, an SRED that treats or prevents age-related and/or inherited retinal dysfunction can modulate intracellular cyclic nucleotide second messenger signaling pathways, by targeting enzymatic catalysis of cyclic nucleotides by select phosphodiesterases. SREDs that target enzymatic catalysis of cyclic nucleotides by select phosphodiesterases can include selective pharmacological inhibitors of PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11, i.e., selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors. SREDs targeting certain PDE subtypes, such as these, hold therapeutic potential to prevent or ameliorate retinal pathology in the context of chronic retinal degenerative diseases, such as AMD, diabetic retinopathy, retinitis pigmentosa, and glaucoma. [0008] In some embodiments, the PDE2 inhibitors can be selected from EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine), BAY 60-7550, PDP (9-(6-phenyl-2-oxohex-3-yl)-2- (3,4-dimethoxybenzyl)-purin-6-one, IC933, oxindole, or any functional analogs thereof. [0009] In other embodiments, the PDE4 inhibitors can be selected from apremilast, arofylline, cilomilast, CL1044, crisaborole, diazepam, drotaverine, filaminast, ibudilast, luteolin, mesopram, mesembrenone, piclamilast, roflumilast (3-(cyclopropylmethoxy)-N- (3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide) and its N-oxide, rolipram, Ro 20- 1724, BAY 19-8004, CC3, AWD 12-281 (N-(3,5-dichloro-4-pyridinyl)-2-[1-(4- fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide), SCH 351591 (N-(3,5-dichloro-1- oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide), ciclamilast, CGH2466, mesembrine, or any functional analogs thereof. [0010] In some embodiments, the PDE5 inhibitors can be selected from Avanafil (4- [(3-chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyr rolidinyl]-N-(2- pyrimidinylmethyl)-5-pyrimidinecarboxamide), Lodenafil (bis-(2-{4-[4-ethoxy-3-(1-methyl- 7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4-,3-d]pyrimidin-5-yl )-benzenesulfonyl]piperazin- 1-yl}-ethyl)carbonate), Mirodenafil (5-ethyl-3,5-dihydro-2-[5-([4-(2-hydroxyethyl)-1- piperazinyl]sulfonyl)-2-propoxyphenyl]-7-propyl-4H-pyrrolo[3 ,2-d]pyrimidin-4-one), Sildenafil citrate (1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyraz olo[4- ,3- d]pyrimidin-5-yl) phenylsulfonyl]-4-methylpiperazine), Tadalafil (6R-trans)-6-(1,3- benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino [1', 2':1,6]pyrido[3,4- b]indole-1,4-dione), Udenafil (3-(1-methyl-7-oxo-3-propyl-4,7-dihydro-1H-pyrazolo[4,3- d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-pro poxybenzenesulfonamide) or any functional analogs thereof. [0011] In some embodiments, the PDE6 inhibitors can be selected from zaprinast, T- 1032, T-0156, or analogs thereof. [0012] In some embodiments, the PDE7 inhibitors can be selected from dipyridamole, BRL-50481, IR-202, quinazoline, or any functional analogs thereof. [0013] In some embodiments, the PDE8 inhibitors can be selected from E-4021, PF- 04957325, or any functional analogs thereof. [0014] In some embodiments, the PDE9 inhibitors can be selected from IMR-687and PF-04447943 or any functional analogs thereof. [0015] In some embodiments, the PDE10 inhibitors can be selected from MP-10, PQ- 10, TP-10, papaverine, or mardepodect hydrochloride or any functional analogs thereof. [0016] In still other embodiments, the PDE11 inhibitors can be selected from BC11-15; BC11-19; BC11-28, BC11-38, and variants of BC11-38, such as BC11-38-1; BC11-38-2; BC11-38-3 and BC11-38-4. [0017] In some embodiments, the SRED can include at least one of a selective inhibitor of PDE2, a selective inhibitor of PDE4, a selective inhibitor of PDE5, a selective inhibitor of PDE6, a selective inhibitor of PDE7, a selective inhibitor of PDE8, a selective inhibitor of PDE9, a selective inhibitor of PDE10, or a selective inhibitor of PDE11. [0018] In other embodiments, the SRED is a selective PDE2 inhibitor, selective PDE4 inhibitor, and/or selective PDE11 inhibitor. [0019] Administration of selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors (e.g., selective PDE2 inhibitors, selective PDE4 inhibitors, and/or PDE11 inhibitors) alone or in combination at a pharmaceutically effective dose, can enhance physiological resilience to stress by promoting intrinsic mechanisms of somatic maintenance and attenuating degenerative processes that drive retinal degeneration and associated pathology. [0020] In some embodiments, the age-related retinal dysfunction can manifest as at least one of the following conditions: autofluorescent spots indicative of retinal pathology detected in the fundus by Scanning Laser Ophthalmoscopy (SLO), thinning of the photoreceptor containing outer nuclear layer (ONL) as characterized by Optical Coherence Tomography (OCT), a global reduction of chromatin accessibility as determined by an Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq), and photoreceptor degeneration. [0021] In some embodiments, the agent is effective to inhibit bright light-induced retinal damage in a Rdh8 ^-/- Abca4 ^-/- mouse. [0022] In some embodiments, the agent can be delivered to the subject by at least one of topical administration, systemic administration, intravitreal injection, and intraocular delivery. [0023] In other embodiments, the agent can be provided in an ocular preparation for sustained delivery. [0024] In some embodiments, the retinal dysfunction is selected from age-related macular degeneration (AMD), such as dry AMD or wet AMD, diabetic retinopathy, retinitis pigmentosa, geographic atrophy, or glaucoma. [0025] Other embodiments, relate to a method of treating and/or preventing stress- induced photoreceptor degeneration or optic neuropathy in a subject in need thereof by administering to the subject a therapeutically effective amount of an SRED that enhances physiological resilience to stress by promoting intrinsic mechanisms of somatic maintenance (e.g., Glul, RdCVF, CREB) and attenuating degenerative processes (e.g., Fas, TNF, HDAC11, C3) that drive retinal degeneration. The stress-induced photoreceptor degeneration can be associated an increase in histone deacetylase and/or histone methyltransferase in the subject’s eye. [0026] In some embodiments, the stress-induced photoreceptor degeneration can manifest as at least one of the following conditions: autofluorescent spots indicative of retinal pathology detected in the fundus by Scanning Laser Ophthalmoscopy (SLO), thinning of the photoreceptor containing outer nuclear layer (ONL) as characterized by Optical Coherence Tomography (OCT), and a global reduction of chromatin accessibility as determined by an Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq). [0027] In some embodiments, the SRED can include at least one of a selective inhibitor of PDE2, a selective inhibitor of PDE4, a selective inhibitor of PDE5, a selective inhibitor of PDE6, a selective inhibitor of PDE7, a selective inhibitor of PDE8, a selective inhibitor of PDE9, a selective inhibitor of PDE10, or a selective inhibitor of PDE11. [0028] In other embodiments, the SRED can include at least one of a selective inhibitor of PDE2, a selective inhibitor of PDE4, or a selective inhibitor of PDE11. [0029] In some embodiments, selective PDE2 inhibitors can include EHNA, BAY 60- 7550, PDP, IC933 or oxindole. [0030] In other embodiments, selective PDE4 inhibitors can include apremilast, arofylline, cilomilast, CL1044, crisaborole, diazepam, drotaverine, filaminast, ibudilast, luteolin, mesopram, mesembrenone, piclamilast, roflumilast, or rolipram. [0031] In still other embodiments, selective PDE11 inhibitors can include BC11-15; BC11-19; BC11-28, BC11-38, and variants of BC11-38, such as BC11-38-1; BC11-38-2; BC11-38-3 and BC11-38-4. BRIEF DESCRIPTION OF THE DRAWINGS [0032] Figs.1(A-D) illustrate PDE expression in murine retina. A) Schematic representation showing domain organization in the eleven cyclic nucleotide PDE families and subtype-specific hydrolysis of cAMP and/or cGMP. The conserved phosphohydrolase catalytic domain is represented in green. Cam, Calmodulin; CamKII, calcium/calmodulin- dependent protein kinase II; cG/cA, cGMP/cAMP domain; PAS, Per-Arnt-Sim; PKG, protein kinase G; TM, transmembrane domain; UCR, upstream conserved region. B) scRNA-seq heat map depicting average expression values of PDE isoforms by cell type in retinas of unstressed control Abca4 ^-/- Rdh8 ^-/- (dKO) mice, measured in normalized unique molecular identifier (nUMI) counts. AC, amacrine cell; As, astrocyte; BC, bipolar cell; RGC, retinal ganglion cell; RPE, retinal pigmented epithelium; vEC/Peri, vascular endothelial cell or pericyte. C) scRNA-seq analysis reveals PDE isoforms become differentially expressed in dKO mice 1 day after exposure to bright-light stress, relative to unstressed controls. logFC, log fold change. D) Cross-sectional diagram of retina, highlighting cell types (red) that exhibit stress- induced upregulation (logFC ≥ 0.5) of PDE2, PDE4, and PDE11 isoforms, respectively. [0033] Figs.2(A-B) illustrate atRAL-induced cytotoxicity in ARPE-19 cells is attenuated by selective PDE inhibitors. A) Immunofluorescence microscopy with Hoechst nuclear staining reveals increased Fluo-3 AM (F3AM) signal in cells exposed to 60 μM atRAL (n = 16) relative to DMSO vehicle-treated controls (n = 16), indicating increased intracellular Ca ²⁺ associated with stress-induced cytotoxicity. Treatment with 10 μM of selective PDE inhibitors BAY 60-7550 (PDE2i; n = 3), rolipram (PDE4i; n = 3), or BC11-38 (PDE11i; n = 5) attenuates Ca ²⁺ -associated cytotoxicity. Scale bars, 100 µm. B) Overall F3AM signal is quantified in relative fluorescence units (RFU). One-way ANOVA, Dunnett's T3 multiple comparisons test; *P < 0.05, ***P = 0.0002, ****P < 0.0001. [0034] Figs.3(A-C) illustrate selective PDE inhibitors mitigate stress-induced retinal degeneration. A) Representative SLO images (top row) reveal autofluorescent puncta in the fundus of DMSO vehicle-treated dKO mice 7 days after exposure to bright-light stress, as compared to unstressed dKO and WT controls. SLO scale bars, 500 μm. OCT images (bottom row) from which thickness of the photoreceptor-containing outer nuclear layer (ONL, yellow asterisk) is measured. OCT scale bars, 50 µm. GCL, ganglion cell layer; INL, inner nuclear layer. n = 3 per group. B) Spider graph of ONL thickness as a function of distance from the optic nerve head (ONH). Combined SLO and OCT imaging analyses reveal dKO mice are protected from stress-induced retinal pathology by treatment with selective PDE inhibitors BAY 60-7550 (PDE2i), rolipram (PDE4i), or BC 11-38 (PDE11i). C) Scotopic ERG recordings demonstrate retinal function impairment in stressed dKO mice (red) relative to unstressed controls (black). Treatment with PDE inhibitors in stressed dKO mice preserved photoreceptor function (a-wave; empty circles) and inner retinal function (b- wave; solid circles) to levels at or above those of unstressed, vehicle-treated controls. Repeated measures two-way ANOVA comparison with negative (black) or positive (red) control groups; ***P = 0.0002, ****P < 0.0001. [0035] Figs.4(A-D) illustrate scRNA-seq analysis of stress resilience mechanisms. A) Clustering of retinal cell types in dKO mice. B) Cell types grouped by experimental condition; unstressed, or 1 day after bright-light stress treated with rolipram (PDE4i) or BC11-38 (PDE11i). C) Average Glul expression in retinal cell types, quantified by normalized unique molecular identifier (UMI) counts, and log fold change (logFC) reveals genes downregulated or upregulated 1 day after stress relative to unstressed controls (Δ Stress); in stressed mice treated with PDEi relative to vehicle-treated controls (Δ PDEi); and in stressed mice treated with PDEi relative to unstressed controls (Net Δ). Cell types exhibiting significant Glul downregulation (Δ Stress) with logFC < -1 are labeled and highlighted in blue in the cross-sectional retina diagram. D) Average Tnfrsf12a expression in retinal cell types, quantified by UMI and logFC. Cell types exhibiting significant Tnfrsf12a upregulation (Δ Stress) with logFC > 1 are labeled and highlighted in red in the cross- sectional retina diagram. [0036] Figs.5(A-C) illustrate stress-induced proteomic and phosphoproteomic dysregulation is attenuated by PDE- inhibitor therapy. A) Quantitative proteomic analysis reveals downregulated (blue) or upregulated (red) proteins, 1 day after bright-light stress exposure (n = 6) relative to unstressed (n = 6) controls (Δ Stress); in stressed dKO mice treated with 2 mg/kg BC11-38 (n = 3) relative to DMSO vehicle- treated controls (Δ PDEi); and in stressed mice treated with BC11-38 relative to unstressed vehicle-treated controls (Net Δ). B) Quantitative Western blot analysis of NXNL1 (RdCVF) expression in unstressed and stressed mice treated with BC11-38 (PDEi) or vehicle. RQ, relative quantity. n = 3 per group, *P < 0.05, ***P < 0.001. C) Quantitative phosphoproteomic analysis reveals hypophosphorylated (blue) or hyperphosphorylated (red) proteins (phospho-sites). n = 3- 6 per group. logFC, log fold change. [0037] Fig.6(A-C) illustrate rolipram treatment attenuates stress-induced apoptosis in retina. A-B) Bulk RNA-seq analysis of retinas collected from dKO mice 6 hours (n = 3), 1 day (n = 4), and 3 days (n = 4) after exposure to bright-light stress reveals significant differentially expressed genes 1 day after stress (adjusted P value < 0.05), confirming A) decreased somatic maintenance (Glul, Nxnl1, Xiap, Tulp1) and B) increased intrinsic (Trp53) and extrinsic (Tnfrsf/Fas) apoptosis, relative to unstressed (NS) controls (n = 6). Boxes and whiskers represent interquartile and minimum- maximum ranges, respectively. CPM, counts per million. C) Immunohistochemistry analysis of retinal cross-sections demonstrates TNFR1 upregulation at the protein level with concomitant degeneration of cone photoreceptors (PNA) in dKO mice 1 day after exposure to stress, relative to unstressed controls. In dKO mice treated with rolipram (PDEi), TNFR1-mediated apoptosis and cone degeneration are mitigated 1 day after exposure to stress, relative to vehicle-treated controls. Sections shown are from the same dorsal region of the retina in each mouse. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; OS, outer segment layer; RPE, retinal pigment epithelium. Scale bars, 50 µm. [0038] Figs.7(A-G) illustrate chronic retinal degeneration is attenuated by long-term rolipram therapy across distinct disease models. A) Representative immunohistochemistry images from rd10 mice at 2 mm dorsal to the optic nerve head (ONH) show increased Fas signaling after two weeks on the control diet, attenuated in mice on the rolipram diet. DAPI labels nuclei, and peanut agglutinin (PNA) labels cone photoreceptors. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; RPE, retinal pigment epithelium. B) Spider graph of ONL thickness as a function of distance from ONH in rd10 mice. n = 4 per group, repeated measures two-way ANOVA (F(1, 6) = 17.04, **P = 0.0062). C) Photopic ERGs from rd10 mice demonstrate improved retinal function on the rolipram diet relative to control. n = 4 per group, two-way ANOVA (F(1, 6) = 7.896, *P = 0.0308). D-G) Rolipram therapy mitigates hallmarks of diabetic retinopathy. Streptozotocin (STZ)-induced diabetic mice exhibited significantly increased D) retinal superoxide, E) inflammatory ICAM1 protein expression, F) leukocyte-mediated cytotoxicity in retinal endothelial cells (EC), and G) degeneration of retinal capillaries, all of which were alleviated by daily rolipram treatment. Rolipram was administered intraperitoneally in DMSO at the indicated doses. Data are expressed as a percentage of the value of non-diabetic controls. n = 5-7 per group, *P < 0.05, **P < 0.01. [0039] Fig.8 illustrates molecular mechanisms of stress resilience enhanced by PDE- inhibitor therapy. Treatment with selective inhibitors of PDE2 (BAY 60-7550; BAY), PDE4 (rolipram; RPM), and PDE11 (BC11-38; BC11) decreases cyclic nucleotide hydrolysis, resulting in increased intracellular concentrations of cAMP and/or cGMP and activation of the PKA/PKG-CREB signaling axis (highlighted in red), which confers a stress-resilient phenotype by stimulating downstream somatic maintenance processes (e.g., Glul, RdCVF, Xiap, Tulp1, pCREB- S133/S271, etc.) that promote cell survival while inhibiting degenerative or apoptotic processes (e.g., Tnfrsf, C3, HDAC11, Trp53, Fas, etc.) that drive cell death. [0040] Figs.9(A-B) illustrate PDE4D upregulation in dKO retina after stress. A) Cross-sectional diagram of retina before and after stress, highlighting cell types (red) that exhibit transcriptional upregulation (logFC ≥ 0.5) of Pde4d 24 hours after bright-light stress. B) Immunohistochemistry analysis of retinal cross-sections confirms increased PDE4D protein expression in retina 24 hours after exposure to stress, relative to unstressed controls. DAPI labels nuclei, and peanut agglutinin (PNA) labels cone photoreceptors. Sections shown are from the same dorsal region of the retina in each mouse. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer; OS, outer segment layer; RPE, retinal pigment epithelium. Scale bars, 50 µm. [0041] Figs.10(A-C) illustrate proteomic analysis of stress resilience mechanisms modulated by selective PDE inhibitors in ARPE-19 cells. A) Functional network map of all proteins either upregulated by both atRAL and oxidative stress and downregulated by all three PDE inhibitors, or downregulated by both types of stress and upregulated by all three PDE inhibitors. B) Pathway analysis of proteins in (A) reveals significantly enriched biological processes. C) Quantitative proteomic analysis measuring differential expression in cells exposed to stress or PDE inhibitors. FDR, false discovery rate; logFC, log fold change. [0042] Figs.11(A-B) illustrate selective PDE inhibitors do not impair PDE6-dependent cGMP hydrolysis in vitro. A) Coomassie staining of the isotonic (Iso), hypotonic (Hypo), and final ([PDE6]f) extraction fractions of bovine ROS used in the PDE6-activity assay. PDE6 comprises approximately one-third of the total protein concentration in the final extraction fraction, while the alpha and beta subunits of transducin (Gtα and Gtβ) each make up one-third, accounting for the remaining two-thirds. B) Fluorescence enzymatic activity assay measuring PDE6-catalyzed cGMP hydrolysis as a function of time (minutes) in the presence of 1 μM rolipram (RPM), BC11- 38 (BC11), vardenafil or DMSO-vehicle. n = 3 replicates per group. [0043] Figs.12(A-B) illustrate visual phototransduction cascade is impaired in vivo by nonspecific PDE inhibitor vardenafil but not by selective PDE inhibitors BAY 60-7550 (BAY), rolipram (RPM), or BC 11-38 (BC11). A) Representative scotopic ERG traces from dKO mice 30 min after intraperitoneal administration of DMSO-vehicle or PDE inhibitors. B) Luminance-response functions for the average (± SEM) amplitude of the a-wave (left) and b-wave (right). [0044] Figs.13(A-D) illustrate proteomic analysis of stress resilience mechanisms modulated by selective PDE inhibitors in dKO mice. A-B) Functional network map of all proteins upregulated 1 day after bright-light stress and downregulated by all three PDE inhibitors (A), or downregulated by stress and upregulated by all three PDE inhibitors (B). n = 3-6 per group. C) Pathway analysis of proteins in (A-B) reveals significantly enriched biological processes. D) Quantitative Western blot analysis of phosphorylated CREB (pCREB) expression in unstressed (NB) and stressed mice (1d) treated with DMSO vehicle or BC11-38 (PDEi). n = 3 per group. RQ, relative quantity. [0045] Fig.14 illustrates representative SLO (left) and OCT (right) images obtained from rd10 mice reared under standard lighting on control versus rolipram-infused diets. n = 8 per group. [0046] Fig.15 illustrates a graph showing protection of retina against 10,000 lux 30 minute lights induced degeneration in Abca ^-/- Rdh8 ^-/- double knock out mice by PDE inhibitors. [0047] Fig.16 illustrates pERG traces of control eyes of mice reared on a base or rolipram-infused diet for one week. [0048] Fig.17 illustrates pERG traces of IOP eyes of mice reared on a base or rolipram-infused diet for one week prior to initiating intraocular pressure (IOP) stress followed by pERG recordings 5-7 days after stress. [0049] Fig.18 illustrates images of retinal ganglion cell in IOP eyes of mice reared on base or rolipram infused diet. [0050] Fig.19 illustrates retinal ganglion cell density in IOP eyes of mice reared on base or rolipram infused diet. [0051] Fig.20 illustrates graphs summarizing pERG Averages of IOP eyes of mice reared on a base or rolipram-infused diet for one week prior to initiating intraocular pressure (IOP) stress followed by pERG recordings 5-7 days after stress. DETAILED DESCRIPTION [0052] For convenience, certain terms employed in the specification, examples, and appended claims are collected here. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. [0053] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. [0054] The terms "comprise," "comprising," "include," "including," "have," and "having" are used in the inclusive, open sense, meaning that additional elements may be included. The terms "such as", "e.g.,", as used herein are non-limiting and are for illustrative purposes only. "Including" and "including but not limited to" are used interchangeably. [0055] The term "or" as used herein should be understood to mean "and/or", unless the context clearly indicates otherwise. [0056] As used herein, the term "about" or "approximately" refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. In one embodiment, the term "about" or "approximately" refers a range of quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, or ± 1% about a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. [0057] The phrases "parenteral administration" and "administered parenterally" are art- recognized terms, and include modes of administration other than enteral and topical administration, such as injections, and include, without limitation, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion. [0058] As used herein, the term "age-related retinal dysfunction” refers to age-related decreases in retinal photoreceptor function. The term is meant to include the age-related impairments related to photoreceptor cell death, structural abnormalities, and retinal pathology that have been observed in both animal and human studies of aging. In one aspect, the age-related retinal dysfunction may manifest as age-related macular degeneration (AMD), which can occur in either wet or dry forms. In another aspect, age-related retinal dysfunction may manifest as other retinal degenerative diseases including diabetic retinopathy (DR), retinitis pigmentosa (RP), and glaucoma. The term “neurodegeneration” as used herein refers to any general neurodegenerative process occurring in age-related disease that involves pathological neuronal cell death. [0059] The term “glaucoma” refers to a group of eye diseases that can cause vision loss and blindness by damaging an optic nerve in the back of the eye. Glaucoma can include primary open angle glaucoma, normal tension glaucoma, hypersecretion glaucoma, acute angle-closure glaucoma, chronic closed angle glaucoma, combined-mechanism glaucoma, corticosteroid glaucoma, amyloid glaucoma, neovascular glaucoma, malignant glaucoma, capsular glaucoma, plateau iris syndrome and drug induced ocular hypertension. [0060] A disease or a condition associated with elevated intraocular pressure includes drug-induced elevated intraocular pressure (i.e., steroid and anti-VEGF induced elevated IOP) that occurs, for example, during the treatment of retinopathies including retinopathy of prematurity, retinal vein occlusion or diabetic macular edema or age-related macular degeneration. [0061] The term "treating" is art-recognized and includes inhibiting a disease, disorder or condition in a subject, e.g., impeding its progress; and relieving the disease, disorder or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected. More specifically, the compounds and methods described herein which are used to treat a subject with age-related or inherited retinal dysfunction generally are provided in a therapeutically effective amount to achieve an improvement in age-related or inherited retinal dysfunction or an inhibited development of age-related or inherited retinal dysfunction in the visual system of a subject, as compared with a comparable visual system not receiving the drug. An improvement in age-related or inherited retinal dysfunction includes long-term (e.g., as measured in weeks or months) improvement or restoration of photoreceptor function in a visual system, as compared with a comparable visual system not receiving the drug. Improvement also includes stabilization of, or minimization of additional degradation in, a vertebrate visual system, as compared with a comparable vertebrate visual system not receiving the drug. [0062] The terms “preventing,” “prevention,” and the like are used generally to mean preventing or inhibiting deterioration or further deterioration of the visual system of an aging subject, as compared with a comparable visual system not receiving the drug. [0063] A "patient," "subject," or "host" to be treated by the subject method may mean either a human or non-human animal, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. [0064] The term "pharmaceutical composition" refers to a formulation containing the disclosed compounds in a form suitable for administration to a subject. In a preferred embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salts thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, inhalational, and the like. Dosage forms for the topical or transdermal administration of a compound described herein includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, nebulized compounds, and inhalants. In a preferred embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required. [0065] The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the term includes compositions, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0066] The phrase "pharmaceutically acceptable carrier" is art-recognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a subject composition and not injurious to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. [0067] The compounds of the application are capable of further forming salts. All of these forms are also contemplated herein. [0068] "Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. For example, the salt can be an acid addition salt. One embodiment of an acid addition salt is a hydrochloride salt. The pharmaceutically acceptable salts can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile being preferred. Lists of salts are found in Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990). [0069] The terms "prophylactic” or “therapeutic" treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). [0070] By "reduces" or "increases" is meant a negative or positive alteration, respectively, of at least 10%, 25%, 50%, 75%, or 100% [0071] The terms “agent”, "therapeutic agent", "drug", "medicament" and "bioactive substance" are art-recognized and include molecules and other agents that are biologically, physiologically, or pharmacologically active substances that act locally or systemically in a patient or subject to treat a disease or condition. The terms include without limitation pharmaceutically acceptable salts thereof and prodrugs. Such agents may be acidic, basic, or salts; they may be neutral molecules, polar molecules, or molecular complexes capable of hydrogen bonding; they may be prodrugs in the form of ethers, esters, amides and the like that are biologically activated when administered into a patient or subject. [0072] The phrase "therapeutically effective amount" or “pharmaceutically effective amount” is an art-recognized term. In certain embodiments, the term refers to an amount of a therapeutic agent that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate, reduce or maintain a target of a particular therapeutic regimen. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular compound without necessitating undue experimentation. [0073] Throughout the description, where compositions are described as having, including, or comprising, specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the compositions and methods described herein remains operable. Moreover, two or more steps or actions can be conducted simultaneously. [0074] The term "small molecule" is an art-recognized term. In certain embodiments, this term refers to a molecule, which has a molecular weight of less than about 2000 amu, or less than about 1000 amu, and even less than about 500 amu. [0075] The terms "IC50," or “half maximal inhibitory concentration” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. [0076] The terms "gene expression" or "protein expression" includes any information pertaining to the amount of gene transcript or protein present in a sample, as well as information about the rate at which genes or proteins are produced or are accumulating or being degraded (e.g., reporter gene data, data from nuclear runoff experiments, pulse-chase data etc.). Certain kinds of data might be viewed as relating to both gene and protein expression. For example, protein levels in a cell are reflective of the level of protein as well as the level of transcription, and such data is intended to be included by the phrase "gene or protein expression information". Such information may be given in the form of amounts per cell, amounts relative to a control gene or protein, in unitless measures, etc.; the term "information" is not to be limited to any particular means of representation and is intended to mean any representation that provides relevant information. The term "expression levels" refers to a quantity reflected in or derivable from the gene or protein expression data, whether the data is directed to gene transcript accumulation or protein accumulation or protein synthesis rates, etc. [0077] The terms "healthy" and "normal" are used interchangeably herein to refer to a subject or particular cell or tissue that is devoid (at least to the limit of detection) of a disease condition. [0078] The term "nucleic acid" refers to polynucleotides such as deoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid (RNA). The term should also be understood to include analogues of either RNA or DNA made from nucleotide analogues, and, as applicable to the embodiment being described, single-stranded (such as sense or antisense) and double-stranded polynucleotides. In some embodiments, "nucleic acid" refers to inhibitory nucleic acids. Some categories of inhibitory nucleic acid compounds include antisense nucleic acids, RNAi constructs, and catalytic nucleic acid constructs. Such categories of nucleic acids are well-known in the art. [0079] The term "retina" refers to a region of the central nervous system with approximately 150 million neurons. It is located at the back of the eye where it rests upon a specialized epithelial tissue called retinal pigment epithelium or RPE. The retina initiates the first stage of visual processing by transducing visual stimuli in specialized neurons called "photoreceptors". Their synaptic outputs are processed by elaborate neural networks in the retina and then transmitted to the brain. The retina has evolved two specialized classes of photoreceptors to operate under a wide range of light conditions. "Rod" photoreceptors transduce visual images under low light conditions and mediate achromatic vision. "Cone" photoreceptors transduce visual images in dim to bright light conditions and mediate both color vision and high acuity vision. [0080] Every photoreceptor is compartmentalized into two regions called the "outer" and "inner" segment. The inner segment is the neuronal cell body containing the cell nucleus. The inner segment survives for a lifetime in the absence of retinal disease. The outer segment is the region where the light sensitive visual pigment molecules are concentrated in a dense array of stacked membrane structures. Part of the outer segment is routinely shed and regrown in a diurnal process called outer segment renewal. Shed outer segments are ingested and metabolized by RPE cells. [0081] The term "macula" refers to the central region of the retina, which contains the fovea where visual images are processed by long slender cones in high spatial detail ("visual acuity"). "Macular degeneration" is a form of retinal neurodegeneration, which attacks the macula and destroys high acuity vision in the center of the visual field. AMD can be in a "dry form" characterized by residual lysosomal granules called lipofuscin in RPE cells, and by extracellular deposits called "drusen". Drusen contain cellular waste products excreted by RPE cells. "Lipofuscin" and drusen can be detected clinically by ophthalmologists and quantified using fluorescence techniques. They can be the first clinical signs of macular degeneration. [0082] Lipofuscin contains aggregations of A2E. Lipofuscin accumulates in RPE cells and poisons them by multiple known mechanisms. As RPE cells become poisoned, their biochemical activities decline and photoreceptors begin to degenerate. Extracellular drusen may further compromise RPE cells by interfering with their supply of vascular nutrients. Drusen also trigger inflammatory processes, which leads to choroidal neovascular invasions of the macula in one patient in ten who progresses to wet form AMD. Both the dry form and wet form progress to blindness. [0083] The term "ERG" is an acronym for electroretinogram, which is the measurement of the electric field potential emitted by retinal neurons during their response to an experimentally defined light stimulus. ERG is a non-invasive measurement, which can be performed on either living subjects (human or animal) or a hemisected eye in solution that has been removed surgically from a living animal. [0084] All percentages and ratios used herein, unless otherwise indicated, are by weight. [0085] Embodiments described herein relate to compositions that include stress resilience-enhancing drugs (SREDs) and their use in treating and/or preventing acute and/or chronic forms retinal dysfunction including, for example, age-related or inherited retinal dysfunction and/or age-related or inherited visual impairment and, particularly, acute and/or chronic retinal degenerative diseases, such as age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, and glaucoma. [0086] We conducted integrative transcriptomic, proteomic, and phosphoproteomic analyses to identify conserved molecular mechanisms in various models of age-related and inherited retinal degeneration, characterized by impaired resilience to stress. For instance, in the Abca4 ^-/- Rdh8 ^-/- double knock (dKO) model that recapitulates hallmarks of AMD, unbiased screening by single cell RNA-seq (scRNA-seq) initially identified glutamine synthetase (Glul) expression, particularly in Müller glia, microglia, astrocytes, and retinal pigment epithelium (RPE). Likewise, unbiased proteome-wide screening revealed that expression of rod-derived cone viability factor (RdCVF) was depleted in degenerating retina, consistent with its previously characterized role in promoting photoreceptor survival; in the context of retinitis pigmentosa, restoration of RdCVF expression by gene therapy has been shown to alleviate cone cell death and improve retinal function. Conversely, histone deacetylase 11 (HDAC11) and complement C3 (C3) were upregulated in degenerating retina. [0087] It was found the processes mediating stress resilience and degeneration are integrally regulated by cyclic nucleotide signaling and can be therapeutically targeted with selective phosphodiesterase (PDE)-inhibitor therapy. Selective PDE inhibitor therapy was found to enhance resilience to stress through synergistic upregulation of somatic maintenance mechanisms (e.g., Glul, RdCVF, Xiap, Tulp1, pCREB-S133/S271) and attenuation of degenerative pathways (e.g., TNF, C3, HDAC11, Trp53, Fas). The results from our combined in vitro and in vivo studies indicate that selective PDE inhibition confers protection across various models of age-related and inherited retinal degeneration. Selective PDE inhibitions can enhance conserved mechanisms of stress resilience and can be used to treat the most common causes of blindness, irrespective of specific disease etiology or underlying genetic mutations. [0088] Accordingly, a method of treating and/or preventing retinal dysfunction in a subject in need thereof can include administering to the subject a therapeutically effective amount of an SRED that can enhance physiological resilience to stress by promoting intrinsic mechanisms of somatic maintenance (e.g., Glul, RdCVF, CREB) and attenuating degenerative processes (e.g., Fas, TNF, HDAC11, C3) that drive retinal degeneration and associated pathology and treat and/or prevent the retinal dysfunction in the subject. [0089] In some embodiments, an SRED that treats or prevents age-related and/or inherited retinal dysfunction can modulate intracellular cyclic nucleotide second messenger signaling pathways, by targeting enzymatic catalysis of cyclic nucleotides by select phosphodiesterases. SREDs that target enzymatic catalysis of cyclic nucleotides by select phosphodiesterases can include selective pharmacological inhibitors of PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11, i.e., selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors. SREDs targeting certain PDE subtypes, such as these, hold therapeutic potential to prevent or ameliorate retinal pathology in the context of chronic retinal degenerative diseases, such as AMD, diabetic retinopathy, retinitis pigmentosa, and glaucoma. [0090] Administration of the selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors alone or in combination at a pharmaceutically effective dose, can enhance physiological resilience to stress by promoting intrinsic mechanisms of somatic maintenance and attenuating degenerative processes that drive retinal degeneration and associated pathology. [0091] In some embodiments, the subject is an aging subject, such as a human, suffering from age-related or inherited retinal dysfunction. For example, an aging human subject is typically at least 45, or at least 50, or at least 60, or at least 65 years old. The subject can have an aging eye, which is characterized as having the retinal dysfunction. [0092] In some embodiments, the retinal dysfunction may be manifested by one or more of the following conditions: autofluorescent spots indicative of retinal pathology detected in the fundus by Scanning Laser Ophthalmoscopy (SLO), thinning of the photoreceptor containing outer nuclear layer (ONL) as characterized by Optical Coherence Tomography (OCT), a global reduction of chromatin accessibility as determined by an Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq), and stress-induced photoreceptor degeneration modeling the pathogenesis of age-related macular degeneration (AMD). [0093] In some embodiments, the age-related or inherited retinal dysfunction can include and/or be associated with, for example, retinal degeneration, macular degeneration, including age-related macular degeneration including the dry form and the wet form of age related macular degeneration, Stargardt’s disease, Stargardt macular degeneration, fundus flavimaculatus, geographic atrophy, retinitis pigmentosa, ABCA4 mutation related retinal dystrophies, vitelliform (or Best) macular degeneration, adult onset form of vitelliform macular dystrophy, Sorsby's fundus dystrophy, Malattia leventinese (Doyne honeycomb or dominant radial drusen), diabetic retinopathy, diabetic maculopathy, diabetic macular edema, retinopathy that is or presents geographic atrophy and/or photoreceptor degeneration, retinopathy that is a lipofuscin-based retinal degeneration, aberrant modulation of lecithin- retinol acyltransferase in an eye, Leber’s congenital amaurosis, retinal detachment, hemorrhagic retinopathy, hypertensive retinopathy, hereditary or non-hereditary optic neuropathy, inflammatory retinal disease, retinal blood vessel occlusion, retinopathy of prematurity, ischemia reperfusion related retinal injury, proliferative vitreoretinopathy, retinal dystrophy, uveitis, retinal disorders associated with Alzheimer's disease, retinal disorders associated with multiple sclerosis, retinal disorders associated with Parkinson's disease, retinal disorders associated with viral infection (cytomegalovirus or herpes simplex virus), retinal disorders related to light overexposure or myopia, retinal disorders associated with AIDS, glaucoma, genetic retinal dystrophies, traumatic injuries to the optic nerve, such as by physical injury, excessive light exposure, or laser light, neuropathies due to a toxic agent or caused by adverse drug reactions or vitamin deficiency, progressive retinal atrophy or degeneration, retinal diseases or disorders resulting from mechanical injury, chemical or drug-induced injury, thermal injury, radiation injury, light injury, or laser injury, hereditary and non-hereditary retinal dystrophy, ophthalmic injuries from environmental factors, such as light-induced oxidative retinal damage, laser-induced retinal damage, "flash bomb injury," or "light dazzle", refractive errors including but not limited to myopia, and retinal diseases related to A2E accumulation including RDS/PHRP2- related macular degeneration, Batten disease (juvenile neuronal ceroid lipofuscinosis), and central serous chorioretinopathy. [0094] In some embodiment, the concentration of a particular selective PDE inhibitor (e.g., selective PDE2 inhibitor, selective PDE4 inhibitor, selective PDE5 inhibitor, selective PDE6 inhibitor, selective PDE7 inhibitor, selective PDE8 inhibitor, selective PDE9 inhibitor, selective PDE10 inhibitor or selective PDE 11 inhibitor) in vitro that inhibits PDE activity by 50% is known as the IC50 value. Selective PDE inhibitors are often referred to by the PDE type that is most specifically inhibited. For example, a PDE2 inhibitor has an IC50 for PDE2 that is lower than the IC50 for any of the other PDEs. A suitable assay for determining the IC50 value of a compound for a PDE is given in Ceyhan et al (2012: Chemistry & Biology 19, 155-163: DOI 10.1016/j.chembio1.2011.12.010). Assays to determine the IC50 of compounds for specific PDE proteins are also commercially available, see for instance BPS Bioscience (PDE2A=Catalog #: 60321) and PDE11A=Catalog #: 60411). [0095] Selective PDE inhibitors can be termed selective based on the fact that other PDE isoforms are only inhibited at higher concentrations. The inhibitor is a selective PDE inhibitor if it has an IC50 for the respective PDE that is at least 10-fold, 20-fold, 30-fold, 40- fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500- fold, 1,000-fold, 2,000-fold, 3,000-fold lower than the IC50 of more than 5 other human PDEs, preferably more than 8, preferably all other human PDEs. For example, a selective PDE2 inhibitor has an IC50 that is at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, 2,000- fold, 3,000-fold lower than the IC50 of the compound for more than 5 other human PDEs, preferably more than 8, preferably all other human PDEs. [0096] A selective PDE4 inhibitor has an IC50 that is at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold lower than the IC50 of the compound for more than 5 other human PDEs, preferably more than 8, preferably all other human PDEs. [0097] A selective PDE5 inhibitor has an IC50 that is at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold lower than the IC50 of the compound for more than 5 other human PDEs, preferably more than 8, preferably all other human PDEs. [0098] A selective PDE6 inhibitor has an IC50 that is at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold lower than the IC50 of the compound for more than 5 other human PDEs, preferably more than 8, preferably all other human PDEs. [0099] A selective PDE7 inhibitor has an IC50 that is at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold lower than the IC50 of the compound for more than 5 other human PDEs, preferably more than 8, preferably all other human PDEs. [00100] A selective PDE8 inhibitor has an IC50 that is at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold lower than the IC50 of the compound for more than 5 other human PDEs, preferably more than 8, preferably all other human PDEs. [00101] A selective PDE9 inhibitor has an IC50 that is at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold lower than the IC50 of the compound for more than 5 other human PDEs, preferably more than 8, preferably all other human PDEs. [00102] A selective PDE10 inhibitor has an IC50 that is at least 10-fold, 20-fold, 30- fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400- fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold lower than the IC50 of the compound for more than 5 other human PDEs, preferably more than 8, preferably all other human PDEs. [00103] A selective PDE11 inhibitor has an IC50 that is at least 10-fold, 20-fold, 30- fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400- fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold lower than the IC50 of the compound for more than 5 other human PDEs, preferably more than 8, preferably all other human PDEs. [00104] In other words, a small molecule selective PDE 2 inhibitor is at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300- fold, 400-fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold, or more selective for inhibition of PDE 2 over one, two, three, four, five, six, seven, eight, or more other PDE isoforms (e.g., PDE 3, PDE 4, PDE 5, PDE 6, PDE 7, PDE 8, PDE 9, PDE 10, or PDE 11). [00105] A small molecule selective PDE 4 inhibitor is at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold, or more selective for inhibition of PDE 2 over one, two, three, four, five, six, seven, eight, or more other PDE isoforms (e.g., PDE 2, PDE 3, PDE 5, PDE 6, PDE 7, PDE 8, PDE 9, PDE 10, or PDE 11). [00106] A small molecule selective PDE 5 inhibitor is at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold, or more selective for inhibition of PDE 5 over one, two, three, four, five, six, seven, eight, or more other PDE isoforms (e.g., PDE 2, PDE 3, PDE 4, PDE 6, PDE 7, PDE 8, PDE 9, PDE 10, or PDE 11). [00107] A small molecule selective PDE 6 inhibitor is at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold, or more selective for inhibition of PDE 2 over one, two, three, four, five, six, seven, eight, or more other PDE isoforms (e.g., PDE 2, PDE 3, PDE4, PDE 5, PDE 7, PDE 8, PDE 9, PDE 10, or PDE 11). [00108] A small molecule selective PDE 7 inhibitor is at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold, or more selective for inhibition of PDE 2 over one, two, three, four, five, six, seven, eight, or more other PDE isoforms (e.g., PDE 2, PDE 3, PDE4, PDE 5, PDE 6, PDE 8, PDE 9, PDE 10, or PDE 11). [00109] A small molecule selective PDE 8 inhibitor is at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold, or more selective for inhibition of PDE 2 over one, two, three, four, five, six, seven, eight, or more other PDE isoforms (e.g., PDE 2, PDE 3, PDE4, PDE 5, PDE 6, PDE 7, PDE 9, PDE 10, or PDE 11). [00110] A small molecule selective PDE 9 inhibitor is at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold, or more selective for inhibition of PDE 2 over one, two, three, four, five, six, seven, eight, or more other PDE isoforms (e.g., PDE 2, PDE 3, PDE4, PDE 5, PDE 6, PDE 7, PDE 8, PDE 10, or PDE 11). [00111] A small molecule selective PDE 10 inhibitor is at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold, or more selective for inhibition of PDE 2 over one, two, three, four, five, six, seven, eight, or more other PDE isoforms (e.g., PDE 2, PDE 3, PDE4, PDE 5, PDE 6, PDE 7, PDE 8, PDE 9, or PDE 11). [00112] A small molecule selective PDE 11 inhibitor is at least 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, 2,000-fold, 3,000-fold, or more selective for inhibition of PDE 2 over one, two, three, four, five, six, seven, eight, or more other PDE isoforms (e.g., PDE 2, PDE 3, PDE 4, PDE 5, PDE 6, PDE 7, PDE 8, PDE 9, PDE 10, or PDE 11). [00113] In certain embodiments, the selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors used in the methods described herein inhibit, respectively, PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11 expression and/or activity. For example, such selective PDE2 inhibitor, selective PDE4 inhibitor, selective PDE5 inhibitor, selective PDE6 inhibitor, selective PDE7 inhibitor, selective PDE8 inhibitor, selective PDE9 inhibitor, selective PDE10 inhibitor or selective PDE 11 inhibitor specifically reduces or inhibits, respectively, activity and/or ability of phosphodiesterase to degrade phosphodiester bonds in second messenger molecules of cyclic nucleotide, such as cAMP and cGMP. In some embodiments, SREDs that modulate (e.g., inhibit) PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11 are polynucleotides, polypeptides, peptides, peptide nucleic acids, antibodies and fragments thereof, small molecules, inorganic compounds and/or organic compounds. [00114] In some embodiments, SREDs that modulate (e.g., inhibit) PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11 are chemical compounds, including large or small inorganic or organic molecules. [00115] Selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors, including small organic compounds, may be identified according to routine screening procedures available in the art, e.g., using commercially available libraries of such compounds. Exemplary small molecule selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors are described in further detail below. [00116] In some embodiments, the PDE2 inhibitor can be selected from EHNA (erythro- 9-(2-hydroxy-3-nonyl)adenine), BAY 60-7550, PDP (9-(6-phenyl-2-oxohex-3-yl)-2-(3,4- dimethoxybenzyl)-purin-6-one, IC933, oxindole, or any functional analogs thereof. [00117] In other embodiments, the PDE4 inhibitors can be selected from apremilast, arofylline, cilomilast, CL1044, crisaborole, diazepam, drotaverine, filaminast, ibudilast, luteolin, mesopram, mesembrenone, piclamilast, roflumilast (3-(cyclopropylmethoxy)-N- (3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide) and its N-oxide, rolipram, Ro 20- 1724, BAY 19-8004, CC3, AWD 12-281 (N-(3,5-dichloro-4-pyridinyl)-2-[1-(4- fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide), SCH 351591 (N-(3,5-dichloro-1- oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide), ciclamilast, CGH2466, mesembrine, or any functional analogs thereof. [00118] In some embodiments, the PDE5 inhibitor can be selected from Avanafil (4-[(3- chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrroli dinyl]- -N-(2- pyrimidinylmethyl)-5-pyrimidinecarboxamide), Lodenafil (bis-(2-{4-[4-ethoxy-3-(1-methyl- 7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4- ,3-d]pyrimidin-5-yl)-benzenesulfonyl]piperazin- 1-yl}-ethyl)carbonate), Mirodenafil (5-ethyl-3,5-dihydro-2-[5-([4-(2-hydroxyethyl)-1- piperazinyl]sulfonyl)-2-- propoxyphenyl]-7-propyl-4H-pyrrolo[3,2-d]pyrimidin-4-one), Sildenafil citrate (1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyraz olo[4- ,3- d]pyrimidin-5-yl) phenylsulfonyl]-4-methylpiperazine), Tadalafil (6R-trans)-6-(1,3- benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyr- azino[1', 2':1,6]pyrido[3,4- b]indole-1,4-dione), Udenafil (3-(1-methyl-7-oxo-3-propyl-4,7-dihydro-1H-pyrazolo[4,3- d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-pro poxybenzenesulfonamide) or any functional analogs thereof. [00119] In some embodiments, the PDE6 inhibitor can be selected from zaprinast, T- 1032, T-0156, or analogs thereof. [00120] In some embodiments, the PDE7 inhibitor can be selected from dipyridamole, BRL-50481, IR-202, quinazoline, or any functional analogs thereof. [00121] In some embodiments, the PDE8 inhibitor can be selected from E-4021, PF- 4957325, or any functional analogs thereof. [00122] In some embodiments, the PDE9 inhibitor can be selected from IMR-687and PF-04447943 or any functional analogs thereof. [00123] In some embodiments, the PDE10 inhibitor can be selected from MP-10, PQ-10, TP-10, papaverine, or mardepodect hydrochloride or any functional analogs thereof. [00124] In still other embodiments, the PDE11 inhibitor can be selected from BC11-15; BC11-19; BC11-28, BC11-38, and variants of BC11-38, such as BC11-38-1; BC11-38-2; BC11-38-3 and BC11-38-4. [00125] It will be appreciated that the selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, PDE9 inhibitors, selective PDE10 inhibitors and/or selective PDE 11 inhibitors used in the methods described herein need not be limited to small molecules and that any selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, PDE9 inhibitors, selective PDE10 inhibitors and/or selective PDE 11 inhibitors known in the art may be used. Such other selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, PDE9 inhibitors, selective PDE10 inhibitors and/or selective PDE 11 inhibitors can include dominant negative inhibitors of PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11 which reduce or block the activity of wild type PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11, various polynucleotides for use as inhibitors of PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11 expression and/or activity, such as antisense RNA, RNA interference (RNAi) reagents, or short- interfering RNAs (siRNA), designed to specifically inhibit expression PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11, CRISPR gene editing system used to silence, enhance or mutate the PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11 gene, and antibody agents that specifically bind PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11. [00126] In some embodiments, the selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, PDE9 inhibitors, selective PDE10 inhibitors and/or selective PDE 11 inhibitors can include agents that reduce or inhibits PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11expression, such as PDE2 expression, PDE4 expression, or PDE11 expression, in tissue or cells of a subject in need thereof. [00127] In some embodiments, the agent can include an RNAi construct that inhibits or reduces expression of PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11 in a cell. RNAi constructs comprise double stranded RNA that can specifically block expression of a target gene. [00128] As used herein, the term "dsRNA" refers to siRNA molecules or other RNA molecules including a double stranded feature and able to be processed to siRNA in cells, such as hairpin RNA moieties. [00129] The term "loss-of-function," as it refers to genes inhibited by the subject RNAi method, refers to a diminishment in the level of expression of a gene when compared to the level in the absence of RNAi constructs. [00130] As used herein, the phrase "mediates RNAi" refers to (indicates) the ability to distinguish which RNAs are to be degraded by the RNAi process, e.g., degradation occurs in a sequence-specific manner rather than by a sequence-independent dsRNA response, e.g., a PKR response. [00131] As used herein, the term "RNAi construct" is a generic term used throughout the specification to include small interfering RNAs (siRNAs), hairpin RNAs, and other RNA species, which can be cleaved in vivo to form siRNAs. RNAi constructs herein also include expression vectors (also referred to as RNAi expression vectors) capable of giving rise to transcripts which form dsRNAs or hairpin RNAs in cells, and/or transcripts which can produce siRNAs in vivo. [00132] "RNAi expression vector" (also referred to herein as a "dsRNA-encoding plasmid") refers to replicable nucleic acid constructs used to express (transcribe) RNA which produces siRNA moieties in the cell in which the construct is expressed. Such vectors include a transcriptional unit comprising an assembly of (1) genetic element(s) having a regulatory role in gene expression, for example, promoters, operators, or enhancers, operatively linked to (2) a "coding" sequence which is transcribed to produce a double- stranded RNA (two RNA moieties that anneal in the cell to form an siRNA, or a single hairpin RNA which can be processed to an siRNA), and (3) appropriate transcription initiation and termination sequences. [00133] The choice of promoter and other regulatory elements generally varies according to the intended host cell. In general, expression vectors of utility in recombinant DNA techniques are often in the form of "plasmids" which refer to circular double stranded DNA loops, which, in their vector form are not bound to the chromosome. In the present specification, "plasmid" and "vector" are used interchangeably as the plasmid is the most commonly used form of vector. However, the application describes other forms of expression vectors that serve equivalent functions and which become known in the art subsequently hereto. [00134] The RNAi constructs contain a nucleotide sequence that hybridizes under physiologic conditions of the cell to the nucleotide sequence of at least a portion of the mRNA transcript for the gene to be inhibited (i.e., the "target" gene). The double-stranded RNA need only be sufficiently similar to natural RNA that it has the ability to mediate RNAi. Thus, embodiments tolerate sequence variations that might be expected due to genetic mutation, strain polymorphism or evolutionary divergence. The number of tolerated nucleotide mismatches between the target sequence and the RNAi construct sequence is no more than 1 in 5 base pairs, or 1 in 10 base pairs, or 1 in 20 base pairs, or 1 in 50 base pairs. Mismatches in the center of the siRNA duplex are most critical and may essentially abolish cleavage of the target RNA. In contrast, nucleotides at the 3' end of the siRNA strand that is complementary to the target RNA do not significantly contribute to specificity of the target recognition. [00135] Sequence identity may be optimized by sequence comparison and alignment algorithms known in the art and calculating the percent difference between the nucleotide sequences by, for example, the Smith-Waterman algorithm as implemented in the BESTFIT software program using default parameters (e.g., University of Wisconsin Genetic Computing Group). Greater than 90% sequence identity, or even 100% sequence identity, between the inhibitory RNA and the portion of the target gene is preferred. Alternatively, the duplex region of the RNA may be defined functionally as a nucleotide sequence that is capable of hybridizing with a portion of the target gene transcript. [00136] Production of RNAi constructs can be carried out by chemical synthetic methods or by recombinant nucleic acid techniques. Endogenous RNA polymerase of the treated cell may mediate transcription in vivo, or cloned RNA polymerase can be used for transcription in vitro. The RNAi constructs may include modifications to either the phosphate-sugar backbone or the nucleoside, e.g., to reduce susceptibility to cellular nucleases, improve bioavailability, improve formulation characteristics, and/or change other pharmacokinetic properties. For example, the phosphodiester linkages of natural RNA may be modified to include at least one of a nitrogen or sulfur heteroatom. Modifications in RNA structure may be tailored to allow specific genetic inhibition while avoiding a general response to dsRNA. Likewise, bases may be modified to block the activity of adenosine deaminase. The RNAi construct may be produced enzymatically or by partial/total organic synthesis, a modified ribonucleotide can be introduced by in vitro enzymatic or organic synthesis. [00137] Methods of chemically modifying RNA molecules can be adapted for modifying RNAi constructs (see for example, Nucleic Acids Res, 25:776-780; J Mol Recog 7:89-98; Nucleic Acids Res 23:2661-2668; Antisense Nucleic Acid Drug Dev 7:55-61). Merely to illustrate, the backbone of an RNAi construct can be modified with phosphorothioates, phosphoramidate, phosphodithioates, chimeric methylphosphonate-phosphodiesters, peptide nucleic acids, 5-propynyl-pyrimidine containing oligomers or sugar modifications (e.g., 2'-substituted ribonucleosides, a-configuration). [00138] The double-stranded structure may be formed by a single self-complementary RNA strand or two complementary RNA strands. RNA duplex formation may be initiated either inside or outside the cell. The RNA may be introduced in an amount, which allows delivery of at least one copy per cell. Higher doses (e.g., at least 5, 10, 100, 500 or 1000 copies per cell) of double-stranded material may yield more effective inhibition, while lower doses may also be useful for specific applications. Inhibition is sequence-specific in that nucleotide sequences corresponding to the duplex region of the RNA are targeted for genetic inhibition. [00139] In certain embodiments, the subject RNAi constructs are "small interfering RNAs" or "siRNAs." These nucleic acids are around 19-30 nucleotides in length, and even more preferably 21-23 nucleotides in length, e.g., corresponding in length to the fragments generated by nuclease "dicing" of longer double-stranded RNAs. The siRNAs are understood to recruit nuclease complexes and guide the complexes to the target mRNA by pairing to the specific sequences. As a result, the target mRNA is degraded by the nucleases in the protein complex. In a particular embodiment, the 21-23 nucleotides siRNA molecules comprise a 3' hydroxyl group. [00140] The siRNA molecules described herein can be obtained using a number of techniques known to those of skill in the art. For example, the siRNA can be chemically synthesized or recombinantly produced using methods known in the art. For example, short sense and antisense RNA oligomers can be synthesized and annealed to form double-stranded RNA structures with 2-nucleotide overhangs at each end (Proc Natl Acad Sci USA, 98:9742- 9747; EMBO J, 20:6877-88). These double-stranded siRNA structures can then be directly introduced to cells, either by passive uptake or a delivery system of choice, such as described below. [00141] In certain embodiments, the siRNA constructs can be generated by processing of longer double-stranded RNAs, for example, in the presence of the enzyme dicer. In one embodiment, the Drosophila in vitro system is used. In this embodiment, dsRNA is combined with a soluble extract derived from Drosophila embryo, thereby producing a combination. The combination is maintained under conditions in which the dsRNA is processed to RNA molecules of about 21 to about 23 nucleotides. [00142] The siRNA molecules can be purified using a number of techniques known to those of skill in the art. For example, gel electrophoresis can be used to purify siRNAs. Alternatively, non-denaturing methods, such as non-denaturing column chromatography, can be used to purify the siRNA. In addition, chromatography (e.g., size exclusion chromatography), glycerol gradient centrifugation, affinity purification with antibody can be used to purify siRNAs. [00143] In certain embodiments, the RNAi construct is in the form of a hairpin structure (named as hairpin RNA). The hairpin RNAs can be synthesized exogenously or can be formed by transcribing from RNA polymerase III promoters in vivo. Examples of making and using such hairpin RNAs for gene silencing in mammalian cells are described in, for example, Genes Dev, 2002, 16:948-58; Nature, 2002, 418:38-9; RNA, 2002, 8:842-50; and Proc Natl Acad Sci, 2002, 99:6047-52. Preferably, such hairpin RNAs are engineered in cells or in an animal to ensure continuous and stable suppression of a desired gene. It is known in the art that siRNAs can be produced by processing a hairpin RNA in the cell. [00144] In yet other embodiments, a plasmid is used to deliver the double-stranded RNA, e.g., as a transcriptional product. In such embodiments, the plasmid is designed to include a "coding sequence" for each of the sense and antisense strands of the RNAi construct. The coding sequences can be the same sequence, e.g., flanked by inverted promoters, or can be two separate sequences each under transcriptional control of separate promoters. After the coding sequence is transcribed, the complementary RNA transcripts base-pair to form the double-stranded RNA. [00145] PCT application WO01/77350 describes an example of a vector for bi- directional transcription of a transgene to yield both sense and antisense RNA transcripts of the same transgene in a eukaryotic cell. Accordingly, certain embodiments provide a recombinant vector having the following unique characteristics: it comprises a viral replicon having two overlapping transcription units arranged in an opposing orientation and flanking a transgene for an RNAi construct of interest, wherein the two overlapping transcription units yield both sense and antisense RNA transcripts from the same transgene fragment in a host cell. [00146] In some embodiments, a lentiviral vector can be used for the long-term expression of a siRNA, such as a short-hairpin RNA (shRNA), to knockdown expression of the of PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11 in an ocular cell. Although there have been some safety concerns about the use of lentiviral vectors for gene therapy, self-inactivating lentiviral vectors are considered good candidates for gene therapy as they readily transfect mammalian cells. [00147] By way of example, short-hairpin RNA (shRNA) down regulation of PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11 expression can be created using OligoEngene software (OligoEngine, Seattle, WA) to identify sequences as targets of siRNA. The oligo sequences can be annealed and ligated into linearized pSUPER RNAi vector (OligoEngine, Seattle, WA) and transformed in E coli strain DH5α cells. After positive clones are selected, plasmid can be transfected into 293T cells by calcium precipitation. The viral supernatant collected containing shRNA can then be used to infect mammalian cells in order to down regulate PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11. [00148] In another embodiment, the selective PDE2 inhibitor, selective PDE4 inhibitor, selective PDE5 inhibitor, selective PDE6 inhibitor, selective PDE7 inhibitor, selective PDE8 inhibitor, selective PDE9 inhibitor, selective PDE10 inhibitor or selective PDE 11 inhibitor can include antisense oligonucleotides. Antisense oligonucleotides are relatively short nucleic acids that are complementary (or antisense) to the coding strand (sense strand) of the mRNA encoding a particular protein. Although antisense oligonucleotides are typically RNA based, they can also be DNA based. Additionally, antisense oligonucleotides are often modified to increase their stability. [00149] The binding of these relatively short oligonucleotides to the mRNA is believed to induce stretches of double stranded RNA that trigger degradation of the messages by endogenous RNAses. Additionally, sometimes the oligonucleotides are specifically designed to bind near the promoter of the message, and under these circumstances, the antisense oligonucleotides may additionally interfere with translation of the message. Regardless of the specific mechanism by which antisense oligonucleotides function, their administration to a cell or tissue allows the degradation of the mRNA encoding a specific protein. Accordingly, antisense oligonucleotides decrease the expression and/or activity of a particular protein (e.g., PDE2, PDE4, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, or PDE11). [00150] The oligonucleotides can be DNA or RNA or chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded. The oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone, for example, to improve stability of the molecule, hybridization, etc. The oligonucleotide may include other appended groups, such as peptides (e.g., for targeting host cell receptors), or agents facilitating transport across the cell membrane (see, e.g., Proc Natl Acad Sci 86:6553-6556; Proc Natl Acad Sci 84:648-652; PCT Publication No. WO88/09810, published Dec.15, 1988) or the blood-brain barrier (see, e.g., PCT Publication No. WO89/10134, published Apr.25, 1988), hybridization-triggered cleavage agents (See, e.g., BioTechniques 6:958-976) or intercalating agents. (See, e.g., Pharm Res 5:539-549). To this end, the oligonucleotide may be conjugated or coupled to another molecule. [00151] Oligonucleotides described herein may be synthesized by standard methods known in the art, e.g., by use of an automated DNA synthesizer (such as are commercially available from Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligonucleotides may be synthesized by the method of Stein et al. (Nucl. Acids Res.16:3209), methylphosphonate oligonucleotides can be prepared by use of controlled pore glass polymer supports (Proc Natl Acad Sci 85:7448-7451). [00152] The selection of an appropriate oligonucleotide can be performed by one of skill in the art. Given the nucleic acid sequence encoding a particular protein, one of skill in the art can design antisense oligonucleotides that bind to that protein, and test these oligonucleotides in an in vitro or in vivo system to confirm that they bind to and mediate the degradation of the mRNA encoding the particular protein. To design an antisense oligonucleotide that specifically binds to and mediates the degradation of a particular protein, it is important that the sequence recognized by the oligonucleotide is unique or substantially unique to that particular protein. For example, sequences that are frequently repeated across protein may not be an ideal choice for the design of an oligonucleotide that specifically recognizes and degrades a particular message. One of skill in the art can design an oligonucleotide, and compare the sequence of that oligonucleotide to nucleic acid sequences that are deposited in publicly available databases to confirm that the sequence is specific or substantially specific for a particular protein. [00153] A number of methods have been developed for delivering antisense DNA or RNA to cells; e.g., antisense molecules can be injected directly into the tissue site, or modified antisense molecules, designed to target the desired cells (e.g., antisense linked to peptides or antibodies that specifically bind receptors or antigens expressed on the target cell surface) can be administered systematically. [00154] However, it may be difficult to achieve intracellular concentrations of the antisense oligonucleotide sufficient to suppress translation on endogenous mRNAs in certain instances. Therefore, another approach utilizes a recombinant DNA construct in which the antisense oligonucleotide is placed under the control of a strong pol III or pol II promoter. For example, a vector can be introduced in vivo such that it is taken up by a cell and directs the transcription of an antisense RNA. Such a vector can remain episomal or become chromosomally integrated, as long as it can be transcribed to produce the desired antisense RNA. Such vectors can be constructed by recombinant DNA technology methods standard in the art. Vectors can be plasmid, viral, or others known in the art, used for replication and expression in mammalian cells. [00155] Expression of the sequence encoding the antisense RNA can be by a promoter known in the art to act in mammalian, preferably human cells. Such promoters can be inducible or constitutive. Such promoters include but are not limited to: the SV40 early promoter region (Nature 290:304-310), the promoter contained in the 3' long terminal repeat of Rous sarcoma virus (Cell 22:787-797), the herpes thymidine kinase promoter (Proc Natl Acad Sci 78:1441-1445), the regulatory sequences of the metallothionein gene (Nature 296:39-42), etc. A type of plasmid, cosmid, YAC or viral vector can be used to prepare the recombinant DNA construct that can be introduced directly into the tissue site. Alternatively, viral vectors can be used which selectively infect the desired tissue, in which case administration may be accomplished by another route (e.g., systematically). [00156] In some embodiments, the selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors that can inhibit retinal degeneration upon administration to a subject can be selected using an in vivo assays that measure the ability of the selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors to respectively rescue the stress-induced reduction in euchromatin abundance observed in the retina of photobleached dKO Rdh8 ^-/- Abca4 ^-/- mice and attenuate the stress-induced increase in heterochromatin abundance observed in the RPE/choroid of bleached dKO Rdh8 ^-/- Abca4 ^-/- mice. [00157] In some embodiments, the selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors when administered to a Rdh8 ^-/- Abca4 ^-/- mouse increase the optical coherence tomography OCT score of the mouse in comparison to untreated control animal. Additionally, in some embodiments, therapeutic efficacy of the selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors can be determined using an in vitro assay that measures the ability of the selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors to improve viability of photoreceptor or RPE cells treated with the selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors. [00158] The selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors used in methods described herein to treat age-related or inherited retinal dysfunction can be administered to the subject using standard delivery methods including, for example, topical and systemic delivery methods, such as ophthalmic, parenteral, subcutaneous, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, intradermal injections, or by intravitreal injection, subretinal injection, intraocular injection or periocular injection. The particular approach and dosage used for a particular subject depends on several factors including, for example, the general health, weight, and age of the subject. Based on factors such as these, a medical practitioner can select an appropriate approach to treatment. [00159] Treatment according to the method described herein can be altered, stopped, or re-initiated in a subject depending on the status of the retinal dysfunction. Treatment can be carried out as intervals determined to be appropriate by those skilled in the art. For example, the administration can be carried out 1, 2, 3, or 4 times a day. In some embodiments, the compounds can be administered after induction of retinal degeneration has occurred. [00160] The treatment methods can include administering to the subject a therapeutically effective amount of the selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors described herein. Pharmaceutical compositions for use in the methods described herein can have a therapeutically effective amount of the compound or salts thereof in a dosage in the range of .01 to 1,000 mg/kg of body weight of the subject, and more preferably in the range of from about 10 to 100 mg/kg of body weight of the patient. [00161] The overall dosage will be a therapeutically effective amount depending on several factors including the overall health of a subject, the subject’s disease state, severity of the condition, the observation of improvements and the formulation and route of administration of the selected agent(s). Determination of a therapeutically effective amount is within the capability of those skilled in the art. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the subject's condition. [00162] In some embodiments, a therapeutically effective amount of the compound administered to the subject is an amount effective to improve or preserve visual function, inhibit photoreceptor cell death, and/or improve or preserve retinal structure. [00163] In some embodiments, the improvement or preservation in visual function include an improvement or preservation of photopic electroretinogram (ERG) response. In other embodiments, the improvement or preservation in retinal structure is an improvement or preservation of outer nuclear layer (ONL) thickness. [00164] Formulation of the pharmaceutical compounds for use in the modes of administration noted above (and others) are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (18th edition), ed. A. Gennaro, 1990, Mack Publishing Company, Easton, Pa. (also see, e.g., M. J. Rathbone, ed., Oral Mucosal Drug Delivery, Drugs and the Pharmaceutical Sciences Series, Marcel Dekker, Inc., N.Y., U.S.A., 1996; M. J. Rathbone et al., eds., Modified-Release Drug Delivery Technology, Drugs and the Pharmaceutical Sciences Series, Marcel Dekker, Inc., N.Y., U.S.A., 2003; Ghosh et al., eds., Drug Delivery to the Oral Cavity, Drugs and the Pharmaceutical Sciences Series, Marcel Dekker, Inc., N.Y., U.S.A., 2005; and Mathiowitz et al., eds., Bioadhesive Drug Delivery Systems, Drugs and the Pharmaceutical Sciences Series, Marcel Dekker, Inc., N.Y., U.S.A., 1999. [00165] Compounds described herein can be formulated into pharmaceutical compositions containing pharmaceutically acceptable non-toxic excipients and carriers. The excipients are all components present in the pharmaceutical formulation other than the active ingredient or ingredients. Suitable excipients and carriers can be composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects, or unwanted interactions with other medications. Suitable excipients and carriers are those, which are composed of materials that will not affect the bioavailability and performance of the agent. As generally used herein “excipient” includes, but is not limited to surfactants, emulsifiers, emulsion stabilizers, emollients, buffers, solvents, dyes, flavors, binders, fillers, lubricants, and preservatives. Suitable excipients include those generally known in the art such as the “Handbook of Pharmaceutical Excipients”, 4th Ed., Pharmaceutical Press, 2003. [00166] Pharmaceutical compositions can optionally further contain one or more additional proteins as desired, including plasma proteins, proteases, and other biological material, so long as it does not cause adverse effects upon administration to a subject. Suitable proteins or biological material may be obtained from human or mammalian plasma by any of the purification methods known and available to those skilled in the art; from supernatants, extracts, or lysates of recombinant tissue culture, viruses, yeast, bacteria, or the like that contain a gene that expresses a human or mammalian plasma protein which has been introduced according to standard recombinant DNA techniques; or from the fluids (e.g., blood, milk, lymph, urine or the like) or transgenic animals that contain a gene that expresses a human plasma protein which has been introduced according to standard transgenic techniques. [00167] Pharmaceutical compositions can comprise one or more pH buffering compounds to maintain the pH of the formulation at a predetermined level that reflects physiological pH, such as in the range of about 5.0 to about 8.0. The pH buffering compound used in the aqueous liquid formulation can be an amino acid or mixture of amino acids, such as histidine or a mixture of amino acids such as histidine and glycine. Alternatively, the pH buffering compound is preferably an agent which maintains the pH of the formulation at a predetermined level, such as in the range of about 5.0 to about 8.0, and which does not chelate calcium ions. Illustrative examples of such pH buffering compounds include, but are not limited to, imidazole and acetate ions. The pH buffering compound may be present in any amount suitable to maintain the pH of the formulation at a predetermined level. [00168] Pharmaceutical compositions can also contain one or more osmotic modulating agents, i.e., a compound that modulates the osmotic properties (e.g., tonicity, osmolality and/or osmotic pressure) of the formulation to a level that is acceptable to the blood stream and blood cells of recipient individuals. The osmotic modulating agent can be an agent that does not chelate calcium ions. The osmotic modulating agent can be any compound known or available to those skilled in the art that modulates the osmotic properties of the formulation. One skilled in the art may empirically determine the suitability of a given osmotic modulating agent for use in the inventive formulation. Illustrative examples of suitable types of osmotic modulating agents include, but are not limited to: salts, such as sodium chloride and sodium acetate; sugars, such as sucrose, dextrose, and mannitol; amino acids, such as glycine; and mixtures of one or more of these agents and/or types of agents. The osmotic modulating agent(s) maybe present in any concentration sufficient to modulate the osmotic properties of the formulation. [00169] Compositions comprising the SREDs described herein can contain multivalent metal ions, such as calcium ions, magnesium ions and/or manganese ions. Any multivalent metal ion that helps stabilizes the composition and that will not adversely affect recipient individuals may be used. The skilled artisan, based on these two criteria, can determine suitable metal ions empirically and suitable sources of such metal ions are known, and include inorganic and organic salts. [00170] Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of compositions, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer base systems such as polylactides (U.S. Pat. No.3,773,919; European Patent No.58,481), poly(lactide-glycolide), copolyoxalates polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acids, such as poly-D-(-)-3-hydroxybutyric acid (European Patent No.133,988), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, K R. et at, Biopolymers 22: 547-556), poly (2-hydroxyethyl methacrylate) or ethylene vinyl acetate (Langer, ft et at, J. Biomed. Mater. Res.15:267-277; Langer, B. Chem. Tech.12:98-105), and polyanhydrides. [00171] Other examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Delivery systems also include non-polymer systems that are: lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats, such as mono-, di- and tri- glycerides; hydrogel release systems such as biologically-derived bioresorbable hydrogel (i.e., chitin hydrogels or chitosan hydrogels); sylastic systems; peptide based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fined implants; and the like. Specific examples include, but are not limited to: (a) erosional systems in which the agent is contained in a form within a matrix, such as those described in 13.5. U.S. Pat. Nos.4,452,775, 4,667,014, 4,748,034 and 5,239,660 and (b) diffusional systems in which an active component permeates at a controlled rate from a polymer such as described in U.S. Pat. Nos.3,832,253, and 3,854,480. [00172] Compositions including the selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors described herein are particularly suitable for treating retinal dysfunctions, such as age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, and glaucoma. [00173] In one approach, the compositions can be administered through an ocular device suitable for direct implantation into the vitreous of the eye. The compositions may be provided in sustained release compositions, such as those described in, for example, U.S. Pat. Nos.5,672,659 and 5,595,760. Such devices are found to provide sustained controlled release of various compositions to treat the eye without risk of detrimental local and systemic side effects. An object of the ocular method of delivery is to maximize the amount of drug contained in an intraocular device or implant while minimizing its size in order to prolong the duration of the implant. See, e.g., U.S. Pat. Nos.5,378,475; 6,375,972, and 6,756,058 and U.S. Publications 20050096290 and 200501269448. Such implants may be biodegradable and/or biocompatible implants, or may be non-biodegradable implants. [00174] Biodegradable ocular implants are described, for example, in U.S. Patent Publication No.20050048099. The implants may be permeable or impermeable to the active agent, and may be inserted into a chamber of the eye, such as the anterior or posterior chambers or may be implanted in the sclera, transchoroidal space, or an avascularized region exterior to the vitreous. Alternatively, a contact lens that acts as a depot for compositions of the invention may also be used for drug delivery. [00175] In some embodiments, the implant may be positioned over an avascular region, such as on the sclera, so as to allow for transcleral diffusion of the drug to the desired site of treatment, e.g., the intraocular space and macula of the eye. Furthermore, the site of transcleral diffusion is preferably in proximity to the macula. Examples of implants for delivery of a composition of the invention include, but are not limited to, the devices described in U.S. Pat. Nos.3,416,530; 3,828,777; 4,014,335; 4,300,557; 4,327,725; 4,853,224; 4,946,450; 4,997,652; 5,147,647; 164,188; 5,178,635; 5,300,114; 5,322,691; 5,403,901; 5,443,505; 5,466,466; 5,476,511; 5,516,522; 5,632,984; 5,679,666; 5,710,165; 5,725,493; 5,743,274; 5,766,242; 5,766,619; 5,770,592; 5,773,019; 5,824,072; 5,824,073; 5,830,173; 5,836,935; 5,869,079, 5,902,598; 5,904,144; 5,916,584; 6,001,386; 6,074,661; 6,110,485; 6,126,687; 6,146.366; 6,251,090; and 6,299,895, and in WO 01/30323 and WO 01/28474, all of which are incorporated herein by reference. [00176] Other approaches for ocular delivery include the use of liposomes to target a compound described herein to retinal pigment epithelial cells and/or Bruch's membrane. For example, the compound maybe complexed with liposomes in the manner described above, and this compound/liposome complex injected into patients with an ocular disorder, such as retinitis pigmentosa, using intravenous injection to direct the compound to the desired ocular tissue or cell. Directly injecting the liposome complex into the proximity of the retinal pigment epithelial cells or Bruch's membrane can also provide for targeting of the complex with some forms of ocular disorders, such as retinitis pigmentosa. In a specific embodiment, a selective PDE2 inhibitor, selective PDE4 inhibitor, selective PDE5 inhibitor, selective PDE6 inhibitor, selective PDE7 inhibitor, selective PDE8 inhibitor, selective PDE9 inhibitor, selective PDE10 inhibitor or selective PDE 11 inhibitor can be administered via intra-ocular sustained delivery (such as VITRASERT or ENVISION). In a specific embodiment, the compound is delivered by posterior subtenons injection. In another specific embodiment, microemulsion particles containing the compositions of the invention are delivered to ocular tissue to take up lipid from Bruchs membrane, retinal pigment epithelial cells, or both. [00177] Compositions including selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors described herein may also be delivered topically. For topical delivery, the compositions are provided in any pharmaceutically acceptable excipient that is approved for ocular delivery. Preferably, the composition is delivered in drop form to the surface of the eye. For some applications, the delivery of the composition relies on the diffusion of the compounds through the cornea to the interior of the eye. [00178] In one example, selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors described herein can be provided in an ophthalmic preparation that can be administered to the subject’s eye. The ophthalmic preparation can contain selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors in a pharmaceutically acceptable solution, suspension or ointment. Some variations in concentration will necessarily occur, depending on the particular selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors employed, the condition of the subject to be treated and the like, and the person responsible for treatment will determine the most suitable concentration for the individual subject. The ophthalmic preparation can be in the form of a sterile aqueous solution containing, if desired, additional ingredients, for example, preservatives, buffers, tonicity agents, antioxidants, stabilizers, nonionic wetting or clarifying agents, and viscosity increasing agents. [00179] The compositions including the elective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors described herein, as described above, can be administered in effective amounts. The effective amount will depend upon the mode or administration, the particular condition being treated and the desired outcome. It may also depend upon the stage of the condition, the age and physical condition of the subject, the nature of concurrent therapy, if any, and like factors well known to the medical practitioner. For therapeutic applications, it is that amount sufficient to achieve a medically desirable result. [00180] With respect to a subject suffering from age-related retinal dysfunction, an effective amount is amount effective or sufficient to improve or preserve visual function, inhibit photoreceptor cell death, and/or improve or preserve retinal structure. Generally, doses of the compounds would be from about 0.01 mg/kg per day to about 1000 mg/kg (e.g., 0.01, 0.05, 0.1, 0.25, 0.5, 1.0, 5, 10, 15, 20, 25) per day. It is expected that doses ranging from about 50 to about 2000 mg/kg (e.g., 50, 100, 200, 250, 500, 750, 1000, 1250, 1500, 1750, 2000) will be suitable. Lower doses will result from certain forms of administration, such as intravenous administration. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of a composition including the compounds described herein. [00181] In some embodiments, the compounds described herein can be administered to the subject at early stage or mid stage of the age-related retinal dysfunction, such age-related macular degeneration. The age-related macular degeneration course can be conveniently divided into three stages, i.e., the early stage, intermediate stage, and late stage. [00182] In the early stage, AMD involves medium-sized drusen deposits seen upon eye examination. No pigment changes are present, and there is usually no vision loss at this stage of the disease. Early-stage AMD is usually detected upon a routine eye examination by an ophthalmologist (eye doctor) or other healthcare provider. During this initial stage, an ophthalmologist can detect drusen, long before symptoms occur. [00183] Intermediate-stage AMD involves large drusen, or multiple medium-sized drusen and/or pigment changes are present in one or both eyes, upon examination by the ophthalmologist. Pigment changes, also called retinal pigment epithelium (RPE) disturbances, can lead to vision loss. Studies suggest that the RPE is where macular degeneration starts to occur. The function of the RPE is to absorb light and transport nutrients to the retinal cells. Symptoms that commonly occur during the intermediate stage could include subtle changes in vision, but for many people, there are no symptoms yet. Some people begin to see black or gray spots in the center of their visual field, or they may have trouble adjusting from a location with bright light to a dim area. [00184] Late-stage AMD involves either the wet form of AMD or dry AMD; in the late- stage either form of AMD causes distortion of vision and/or vision loss. The wet form of AMD progresses much faster than the dry form, and wet AMD is much more likely to cause vision loss. When central vision loss begins, objects may appear distorted or blurry at first, but in the late-stage of the disease, objects in the middle of your line of vision cannot be seen at all, although in the peripheral field (side vision) objects are usually still visible, but it may be difficult to decipher what they are. In the late-stage of the disease, a person may no longer be able to recognize faces and although they may still have peripheral (side) vision, they may be considered legally blind. [00185] In one embodiment, a subject is diagnosed as having symptoms of age-related retinal dysfunction (such as impaired vision, drusen deposition, pigment changes, light sensitivity, tunnel vision, and loss of peripheral vision to total loss of vision), and then a disclosed compound is administered. In another embodiment, a subject may be identified as being at risk for developing age-related retinal dysfunction (risk factors may include family history or testing positive for a rhodopsin mutation), and then a disclosed compound is administered. In yet another embodiment, a subject may be diagnosed as having age-related retinal dysfunction and then a disclosed compound is administered. In another embodiment, a subject may be identified as being at risk for developing other forms of retinal degeneration in photoreceptor cells, and then the disclosed compound is administered. In some embodiments, a compound is administered prophylactically. In some embodiments, a subject has been diagnosed as having the disease before retinal damage is apparent. In some embodiments, a human subject may know that he or she is in need of the retinal generation treatment or prevention. [00186] In some embodiments, a subject may be monitored for the extent of retinal degeneration. A subject may be monitored in a variety of ways, such as by eye examination, dilated eye examination, fundoscopic examination, visual acuity test, and/or biopsy. Monitoring can be performed at a variety of times. For example, a subject may be monitored after a compound is administered. The monitoring can occur, for example, one day, one week, two weeks, one month, two months, six months, one year, two years, five years, or any other time period after the first administration of a compound. A subject can be repeatedly monitored. In some embodiments, the dose of a compound may be altered in response to monitoring. [00187] Another strategy for treating a subject suffering from a retinal degeneration is to administer a therapeutically effective amount of a compound described herein along with a therapeutically effective amount of an additional anti-retinal degeneration agent or therapy. Examples of anti-retinal degeneration agents or therapies include but are not limited to supplements, such as vitamin A, DHA, and lutein, as well as optic prosthetic devices, gene therapy mechanisms and retinal sheet transplantations. [00188] Those of skill in the art will recognize that the best treatment regimens for using any of the selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors to treat age- related retinal dysfunction can be determined. This is not a question of experimentation, but rather one of optimization, which is routinely conducted in the medical arts. In vivo studies in nude mice often provide a starting point from which to begin to optimize the dosage and delivery regimes. The frequency of the dose or administration will initially be once a week, as has been done in some mice studies. However, this frequency might be optimally adjusted from one day to every two weeks to monthly, depending upon the results obtained front the initial clinical trials and the needs of a particular patient. [00189] Human dosage amounts can initially be determined by extrapolating from the amount of the selective PDE2 inhibitors, selective PDE4 inhibitors, selective PDE5 inhibitors, selective PDE6 inhibitors, selective PDE7 inhibitors, selective PDE8 inhibitors, selective PDE9 inhibitors, selective PDE10 inhibitors or selective PDE 11 inhibitors used in mice, as a skilled artisan recognizes it is routine in the art to modify the dosage for humans compared to animal models. In certain embodiments it is envisioned that the dosage may vary an amount ranging from about 10-1000 mg (e.g., about 20 mg-1,000 mg, 30 mg-1,000 mg, 40 mg-1,000 mg, 50 mg-1,000 mg, 60 mg-1,000 mg, 70 mg-1,000 mg, 80 mg-1,000 mg, 90 mg-1,000 mg, about 10-900 mg, 10-800 mg, 10-700 mg, 10-600 mg, 10-500 mg, 100- 1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 200-1000 mg, 200-900 mg, 200-800 mg, 200-700 mg, 200-600 mg, 200-500 mg, 200-400 mg, 300-1000 mg, 300-900 mg, 300-800 mg, 300-700 mg, 300-600 mg, 300- 500 mg, 400 mg-1,000 mg, 500 mg-1,000 mg, 100 mg-900 mg, 200 mg-800 mg, 300 mg-700 mg, 400 mg-700 mg, and 500 mg-600 mg). In some embodiments, the compound is present in an amount of or greater than about 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg. In some embodiments, the selective PDE2 inhibitor, selective PDE4 inhibitor, selective PDE5 inhibitor, selective PDE6 inhibitor, selective PDE7 inhibitor, selective PDE8 inhibitor, selective PDE9 inhibitor, selective PDE10 inhibitor or selective PDE 11 inhibitor is present in an amount of or less than about 1000 mg, 950 mg, 900 mg, 850 mg, 800 mg, 750 mg, 700 mg, 650 mg, 600 mg, 550 mg, 500 mg, 450 mg, 400 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, or 100 mg. [00190] In other embodiments, a therapeutically effective dosage amount of the selective PDE2 inhibitor, selective PDE4 inhibitor, selective PDE5 inhibitor, selective PDE6 inhibitor, selective PDE7 inhibitor, selective PDE8 inhibitor, selective PDE9 inhibitor, selective PDE10 inhibitor or selective PDE 11 inhibitor may be, for example, about 0.001 mg/kg weight to 500 mg/kg weight, e.g., from about 0.001 mg/kg weight to 400 mg/kg weight, from about 0.001 mg/kg weight to 300 mg/kg weight, from about 0.001 mg/kg weight to 200 mg/kg weight, from about 0.001 mg/kg weight to 100 mg/kg weight, from about 0.001 mg/kg weight to 90 mg/kg weight, from about 0.001 mg/kg weight to 80 mg/kg weight, from about 0.001 mg/kg weight to 70 mg/kg weight, from about 0.001 mg/kg weight to 60 mg/kg weight, from about 0.001 mg/kg weight to 50 mg/kg weight, from about 0.001 mg/kg weight to 40 mg/kg weight, from about 0.001 mg/kg weight to 30 mg/kg weight, from about 0.001 mg/kg weight to 25 mg/kg weight, from about 0.001 mg/kg weight to 20 mg/kg weight, from about 0.001 mg/kg weight to 15 mg/kg weight, from about 0.001 mg/kg weight to 10 mg/kg weight. [00191] In still other embodiments, a therapeutically effective dosage amount of the selective PDE2 inhibitor, selective PDE4 inhibitor, selective PDE5 inhibitor, selective PDE6 inhibitor, selective PDE7 inhibitor, selective PDE8 inhibitor, selective PDE9 inhibitor, selective PDE10 inhibitor or selective PDE 11 inhibitor may be, for example, about 0.0001 mg/kg weight to 0.1 mg/kg weight, e.g. from about 0.0001 mg/kg weight to 0.09 mg/kg weight, from about 0.0001 mg/kg weight to 0.08 mg/kg weight, from about 0.0001 mg/kg weight to 0.07 mg/kg weight, from about 0.0001 mg/kg weight to 0.06 mg/kg weight, from about 0.0001 mg/kg weight to 0.05 mg/kg weight, from about 0.0001 mg/kg weight to about 0.04 mg/kg weight, from about 0.0001 mg/kg weight to 0.03 mg/kg weight, from about 0.0001 mg/kg weight to 0.02 mg/kg weight, from about 0.0001 mg/kg weight to 0.019 mg/kg weight, from about 0.0001 mg/kg weight to 0.018 mg/kg weight, from about 0.0001 mg/kg weight to 0.017 mg/kg weight, from about 0.0001 mg/kg weight to 0.016 mg/kg weight, from about 0.0001 mg/kg weight to 0.015 mg/kg weight, from about 0.0001 mg/kg weight to 0.014 mg/kg weight, from about 0.0001 mg/kg weight to 0.013 mg/kg weight, from about 0.0001 mg/kg weight to 0.012 mg/kg weight, from about 0.0001 mg/kg weight to 0.011 mg/kg weight, from about 0.0001 mg/kg weight to 0.01 mg/kg weight, from about 0.0001 mg/kg weight to 0.009 mg/kg weight, from about 0.0001 mg/kg weight to 0.008 mg/kg weight, from about 0.0001 mg/kg weight to 0.007 mg/kg weight, from about 0.0001 mg/kg weight to 0.006 mg/kg weight, from about 0.0001 mg/kg weight to 0.005 mg/kg weight, from about 0.0001 mg/kg weight to 0.004 mg/kg weight, from about 0.0001 mg/kg weight to 0.003 mg/kg weight, from about 0.0001 mg/kg weight to 0.002 mg/kg weight. In some embodiments, the therapeutically effective dose may be 0.0001 mg/kg weight, 0.0002 mg/kg weight, 0.0003 mg/kg weight, 0.0004 mg/kg weight, 0.0005 mg/kg weight, 0.0006 mg/kg weight, 0.0007 mg/kg weight, 0.0008 mg/kg weight, 0.0009 mg/kg weight, 0.001 mg/kg weight, 0.002 mg/kg weight, 0.003 mg/kg weight, 0.004 mg/kg weight, 0.005 mg/kg weight, 0.006 mg/kg weight, 0.007 mg/kg weight, 0.008 mg/kg weight, 0.009 mg/kg weight, 0.01 mg/kg weight, 0.02 mg/kg weight, 0.03 mg/kg weight, 0.04 mg/kg weight, 0.05 mg/kg weight, 0.06 mg/kg weight, 0.07 mg/kg weight, 0.08 mg/kg weight, 0.09 mg/kg weight, or 0.1 mg/kg weight. The effective dose for a particular individual can be varied (e.g., increased or decreased) over time, depending on the needs of the individual. [00192] In some embodiments, a therapeutically effective dosage of the selective PDE2 inhibitor, selective PDE4 inhibitor, selective PDE5 inhibitor, selective PDE6 inhibitor, selective PDE7 inhibitor, selective PDE8 inhibitor, selective PDE9 inhibitor, selective PDE10 inhibitor or selective PDE 11 inhibitor may be a dosage of 10 μg/kg/day, 50 μg/kg/day, 100 μg/kg/day, 250 μg/kg/day, 500 μg/kg/day, 1000 μg/kg/day or more. In various embodiments, the amount of selective PDE2 inhibitor, selective PDE 4 inhibitor, and/or selective PDE 11 inhibitor or pharmaceutical salt thereof is sufficient to provide a dosage to a patient of between 0.01 μg/kg and 10 μg/kg; 0.1 μg/kg and 5 μg/kg; 0.1 μg/kg and 1000 μg/kg; 0.1 μg/kg and 900 μg/kg; 0.1 μg/kg and 900 μg/kg; 0.1 μg/kg and 800 μg/kg; 0.1 μg/kg and 700 μg/kg; 0.1 μg/kg and 600 μg/kg; 0.1 μg/kg and 500 μg/kg; or 0.1 μg/kg and 400 μg/kg. [00193] In one aspect, a pharmaceutical composition comprising an effective amount of the selective PDE2 inhibitor, selective PDE4 inhibitor, selective PDE5 inhibitor, selective PDE6 inhibitor, selective PDE7 inhibitor, selective PDE8 inhibitor, selective PDE9 inhibitor, selective PDE10 inhibitor or selective PDE 11 inhibitor is administered at least twice. In another aspect, a pharmaceutical composition is administered at least five times. In yet another aspect, a pharmaceutical composition is administered at least 10 times. One of ordinary skill in the art can determine how often to administer the composition based on the particular disease or disorder being treated or how the subject has responded to prior treatments. [00194] As discussed above, the selective PDE2 inhibitor, selective PDE4 inhibitor, selective PDE5 inhibitor, selective PDE6 inhibitor, selective PDE7 inhibitor, selective PDE8 inhibitor, selective PDE9 inhibitor, selective PDE10 inhibitor or selective PDE 11 inhibitor may be administered to a subject in order to treat or prevent macular degeneration and other forms of retinal disease whose etiology involves progressive photoreceptor degeneration in the central retina and epigenetic changes resulting from environmental exposure and chronic stress. Other diseases, disorders, or conditions characterized by such photoreceptor degeneration in the central retina and epigenetic changes in chromatin accessibility may be similarly treated. Said methods comprise locally (e.g., intravitreal injection) or systemically (oral or enteral administration) administering to the eye(s) of the patient a therapeutically effective amount of a composition described herein. In some embodiments, the SREDs (e.g., selective PDE2 inhibitor, selective PDE4 inhibitor, selective PDE5 inhibitor, selective PDE6 inhibitor, selective PDE7 inhibitor, selective PDE8 inhibitor, selective PDE9 inhibitor, selective PDE10 inhibitor or selective PDE 11 inhibitor) are not administered topically to the subject’s eye. [00195] In one embodiment, a subject is diagnosed as having symptoms of macular degeneration, and then a disclosed compound is administered. In another embodiment, a subject may be identified as being at risk for developing macular degeneration (risk factors include a history of smoking, age, female gender, and family history), and then a disclosed compound is administered. In another embodiment, a subject may have dry AMD in both eye, and then a disclosed compound is administered. In another embodiment, a subject may have wet AMD in one eye but dry AMD in the other eye, and then a disclosed compound is administered. In yet another embodiment, a subject may be diagnosed as having Stargardt disease and then a disclosed compound is administered. In another embodiment, a subject is diagnosed as having symptoms of other forms of retinal disease whose etiology involves photoreceptor degeneration in the central retina and epigenetic changes, and then the compound is administered. In another embodiment, a subject may be identified as being at risk for developing other forms of retinal disease whose etiology involves photoreceptor degeneration in the central retina and epigenetic changes, and then the disclosed compound is administered. In some embodiments, a compound is administered prophylactically. In some embodiments, a subject has been diagnosed as having the disease before retinal damage is apparent. In some embodiments, a human subject may know that he or she is in need of the macular generation treatment or prevention. [00196] In some embodiments, the disclosed methods may be combined with other methods for treating or preventing macular degeneration or other forms of retinal disease whose etiology involves photoreceptor degeneration in the central retina and epigenetic changes in chromatin accessibility. For example, a patient may be treated with more than one therapy for one or more diseases or disorders. A patient may have one eye afflicted with dry form AMD, which is treated with one selective PDE inhibitor, and the other eye afflicted with wet form AMD, which is treated with a different selective PDE inhibitor. [00197] Other embodiments relate to methods of treating and controlling ocular hypertension associated with glaucoma, or of treating ocular hypertension or disease or a condition associated with elevated intraocular pressure. Said methods can include locally (e.g., intravitreal injection) or systemically (oral or enteral administration) administering to the eye(s) of the patient a therapeutically effective amount of a composition described herein. In some embodiments, the SREDs (e.g., selective PDE2 inhibitor, selective PDE4 inhibitor, selective PDE5 inhibitor, selective PDE6 inhibitor, selective PDE7 inhibitor, selective PDE8 inhibitor, selective PDE9 inhibitor, selective PDE10 inhibitor or selective PDE 11 inhibitor) are not administered topically to the subject’s eye. [00198] Still other embodiments described herein are directed to a method to reduce intraocular pressure in a patient with normal tension glaucoma. This method comprises locally (e.g., intravitreal injection) or systemically (oral or enteral administration) administering to the affected eye(s) of the patient a therapeutically effective amount of a composition described herein. [00199] The invention is further illustrated by the following example, which is not intended to limit the scope of the claims. Example 1 [00200] Based on the premise that PDEs function as integrative signaling nodes that could be therapeutically targeted in the context of various retinopathies, we investigated the effects of selective PDE-inhibitor therapy on the hallmarks characteristic of age-related and inherited retinal diseases. We conducted in vitro studies utilizing cell culture models, as well as in vivo studies employing several murine models; namely, the photosensitive Abca4 ^-/- Rdh8 ^-/- double- knockout (dKO) mouse, which exhibits epigenetic and pathological hallmarks of human AMD, the streptozotocin model of diabetic retinopathy, and the rd10 model of autosomal recessive retinitis pigmentosa. The goal in each case was to delineate molecular mechanisms pertinent to therapeutic intervention and to determine whether stress resilience could be enhanced pharmacologically via selective PDE inhibition. Here, we report that selective targeting of PDEs, through stabilization of the transcriptome, proteome, and phosphoproteome, enhanced resilience to stress in degenerating retina, facilitating preservation of tissue structure and function across various models of retinal disease. Methods Animals [00201] Male and female WT, Abca4 ^-/- Rdh8 ^-/- (dKO), and rd10 mice at 6 to 8 weeks of age were obtained from The Jackson Laboratory and housed at the University of California, Irvine (UCI) or the Cleveland Clinic Cole Eye Institute. These mice were bred on a pigmented C57BL/6 background and were age- and litter-matched with control mice for all experiments, unless otherwise indicated. All mice were maintained on a standard 12-hour light (≤150 lux)/12-hour dark cycle. Light damage was induced in photosensitive Abca4 ^-/- Rdh8 ^-/- mice by exposure to white light delivered at 10,000 lux (150-W spiral lamp, Commercial Electric, Cleveland, OH) for 30 min. Mice were dark-adapted 24 hr prior to photobleaching, and pupils were dilated with 1% ophthalmic tropicamide 30 min prior to light exposure. Retinal degeneration occurred in rd10 mice while rearing under standard lighting conditions for two weeks; the mice received either a base diet of rodent chow (LabDiet Prolab RMH3000) or the base chow infused with rolipram at a concentration of 100 ppm (LabDiet 5GAT), and body weights were recorded twice per week to confirm that feeding behavior was not affected by the difference between the two diets. Diabetes was induced by five sequential daily intraperitoneal injections of freshly prepared streptozotocin in citrate buffer (pH 4.5) at 60 mg/kg of body weight. Hyperglycemia was verified during the second week after streptozotocin induction, and mice with at least three consecutive measurements of fasting blood glucose >275 mg/dL were classified as diabetic. Body weight was measured weekly, and insulin was administered as needed to prevent weight loss without preventing hyperglycemia and glucosuria. All animal handling procedures and experimental protocols were approved by IACUCs at UCI or the Cleveland Clinic and conformed to recommendations of both the American Veterinary Medical Association Panel on Euthanasia and the Association for Research in Vision and Ophthalmology (ARVO). Live in vivo retinal imaging [00202] In vivo imaging was conducted at UCI and Cole Eye Institute. At UCI, mice were anesthetized by intraperitoneal injection of ketamine (20 mg/mL) with xylazine (1.75 mg/mL), at a dose of 5 µL/g body weight, and pupils were dilated with 1% tropicamide prior to imaging. Ultrahigh-resolution spectral domain OCT (Bioptigen, Research Triangle Park, NC) was performed for cross-sectional imaging of mouse retinas. Briefly, five frames of OCT images were first acquired in the B-mode and then averaged. For quantitative measurements of photoreceptor viability, ONL thickness was measured via the InVivoVue software at a distance of 0.45 mm from the optic nerve head in the temporal retina, where the most severe damage is found in bright light-exposed Abca4 ^-/- Rdh8 ^-/- mice. SLO (Heidelberg Engineering, Heidelberg, Germany) was also performed for whole fundus imaging of mouse retinas, and images were acquired in the autofluorescence mode. Imaging procedures used at Cole Eye Institute have been described in published protocols. Briefly, mice were anesthetized (sodium pentobarbital, 68 mg/kg) and pupils dilated with 1 µl eyedrops comprised of 0.5% tropicamide and 0.5% phenylephrine HCl. The corneal surface was anesthetized with a single application of ~10 µl of 0.5% proparacaine. SD-OCT images of the retina were collected along the horizontal and vertical meridians centered on the optic disk. Each set of orthogonal radial scans (1000 A-scans per B-scan by 10-15 frames) was converted to AVI files and exported to ImageJ with an axial scale of 1 µm/pixel. In ImageJ, each set of B-scans was co-registered and averaged using StackReg/TurboReg plug-ins. The field of view for each image was 0.464 mm (depth) by ~1.4 mm (width). SD-OCT images were obtained from both eyes in the nasal and temporal cardinal directions from the optic nerve head. The thickness of the ONL was measured from AAA to BBB at distances of 250, 500, and 750 µm from the optic nerve for each image. Electroretinography [00203] Electroretinograms were recorded in standard laboratory lighting conditions using one of two systems. At UCI, we used a Celeris rodent ERG device (Diagnosys, Lowell, MA) with some modifications from a previous protocol. The mice were anesthetized with ketamine (100 mg/kg, KetaVed; Bioniche Teoranta, Inverin Co., Galway, Ireland) and xylazine (10 mg/mg, Rompun; Bayer, Shawnee Mission, KS) by intraperitoneal injection, and their pupils were dilated with 1% tropicamide (Tropicamide Ophthalmic Solution USP 1%; Akorn, Lake Forest, IL), and thereafter lubricated with 0.3% hypromellose gel (GenTeal; Alcon, Fort Worth, TX). Light stimulation was produced by an in-house scripted simulation series in Espion software (version 6; Diagnosys). The eyes were stimulated with a green light-emitting diode (LED) (peak 544 nm, bandwidth 160 nm), where the steady rod- suppressing background light consisted of 200 cd/m ² red (peak 630 nm, bandwidth 100 nm) and 100 cd/m ² UV. Four different green light stimulus intensities between 0.3 and 300 cd·sec/m ² were used in ascending order. At Cole Eye Institute, mice were dark-adapted overnight in a temperature- and humidity monitored cabinet. Thirty minutes prior to the ERG session, mice were injected IP with 250 µl of a PDE inhibitor or DMSO vehicle. Mice were then anesthetized with ketamine/xylazine (80/16 mg/kg) diluted in 0.9% saline after which the pupils were dilated (1% tropicamide, 2.5% phenylephrine HCl, 1% cyclopentolate eyedrops) and the corneal surface was anesthetized (1% proparacaine HCl eyedrops). ERGs were obtained from the corneal surface using a thin stainless-steel wire that was coiled at the end and wetted with a small drop of 1% carboxymethylcellulose. The active lead was referenced to a needle electrode placed in the cheek; a second needle electrode placed in the tail served as the ground lead. Flash stimuli (-3.6 to 1.2 log cd s/m ² ) were presented in darkness within an LKC (Gaithersburg, MD) ganzfeld. ERGs were amplified (0.03–1000 Hz), averaged, and then stored using an LKC UTAS E-3000 or Big-Shot signal averaging system. Retina and RPE extraction for transcriptomic analysis [00204] Fresh retina and RPE tissues were harvested from WT and photosensitive Abca4 ^-/- Rdh8 ^-/- mice according to published protocols. [00205] Briefly, under a dissecting microscope, spring scissors were used to puncture the eye and remove the cornea, iris, and lens. Four radial incisions were made every 90 degrees, resulting in a flat and open eye cup, then the retina was dissected from the posterior eye cup using curved tweezers. For bulk RNA-seq analysis, retinas were placed directly in a 1.5 mL microcentrifuge tube containing RNAlater (Qiagen, Hilden, Germany), while the RPE- containing eyecup was placed in a 1.5 mL microcentrifuge tube containing RNAprotect (Qiagen). Total RNA from RPE cells was isolated for bulk RNA-seq, using the simultaneous RPE cell isolation and RNA stabilization (SRIRS) method. Briefly, the RPE/choroid eyecups immersed in RNAprotect were agitated at 10 min intervals for 20 min at room temperature. After the second agitation, the eyecups were removed to minimize choroid contamination, with dissociated RPE cells remaining in solution. Retina and RPE samples in RNAlater and RNAprotect, respectively, were stored at 4°C. Bulk RNA-seq analysis was performed as described previously, and the dataset is available in the NCBI Gene Expression Omnibus (GEO) data repository under accession number GSE153817. For scRNA-seq, retinas were harvested with RPE from the posterior eye cup and dissociated using the Papain Dissociation System (#LK003153, Worthington Biochemical). Four retinas were pooled for each of the experimental groups to prepare single-cell suspensions at a final concentration of 1,000 cells/µl. Single-cell RNA-seq library preparation and data analysis [00206] Freshly dissociated cells (~15,000) from each experimental group were loaded into a 10x Genomics Chromium Single Cell system using v3 chemistry, per manufacturer instructions. Libraries were pooled and sequenced on Illumina NovaSeq6000 with ~500 million reads per library. The pre-processing steps such as generation and demultiplexing of FASTQ files from raw sequencing reads (bclfastq, v2.20), aligning to UCSC mm10 transcriptome, and generating raw count matrices were conducted using Cell Ranger (v6.0.1) with default parameters. Cumulus software v1.5.0 was used to combine expression matrices (76) and to remove cell doublets by Scrublet v0.2.1. The pipelines were run in Terra Cloud Platform, and downstream analysis was performed in the R software package Seurat v3.2.2. Low-quality cells with less than 500 genes detected and all genes expressed in less than 10 cells were filtered out, leaving 26,543 cells and 20,094 genes for analysis. Principal Component (PC) analysis was performed on a submatrix of the top 1,000 most variable genes computed using the function FindVariableGenes in Seurat. Batch effect between experimental conditions was minimzed using the Harmony package to remove non-cell-type- specific factors that may impact clustering. The number of top PCs was assessed by the elbow method, keeping 19 PCs for clustering and data visualization. Cells were clustered using a shared nearest neighbor modularity optimization-based algorithm (FindClusters in Seurat). Cluster-specific genes were computed by FindAllMarkers in Seurat, using the MAST test with number of UMIs detected as a latent variable. The same test was used to identify differentially expressed genes between experimental groups within cell clusters, which were annotated according to retinal cell- type-specific markers. This scRNA-seq dataset has been deposited in the NCBI GEO data repository under accession number GSE208760. Proteomics analyses [00207] ARPE-19 cells for SILAC quantification experiments were grown in medium supplemented with 10% dialyzed bovine serum and heavy ( ¹³ C ¹⁵ N) or light lysine and arginine for 6 passages to completely label cells (Thermo Scientific SILAC Protein Quantitation Kit #A33972). Completely labeled cells were then collected by addition of trypsin and washed with cold PBS. The cell pellets were lysed by addition of UA buffer containing 8 M Urea, 0.1 M Tris- HCl (pH 8.5), protease inhibitor cocktail (Bimake #14001). The pellets were sonicated and then were kept on ice. Protein concentrations of each sample were determined using the Pierce BCA Protein Assay Kit and a standard curve was generated with BSA. Equal protein amounts of each cell lysate were mixed and digested by the filter- aided sample preparation (FASP) method. Murine retinas were harvested from eye cups as described previously and suspended in UA buffer containing protease inhibitor and phosphatase inhibitor (Bimake #15001) cocktails. The suspension was sonicated on ice for 4 min, followed by centrifugation at 12,000 g for 10 min at 4 ^o C. The supernatant was collected and digested by the FASP method. Briefly, the supernatant was transferred into a spin filter column (30 kDa cutoff). Proteins were reduced with 10 mM DTT for 1 hr at 56 ^o C, and alkylated with 20 mM iodoacetic acid for 1 hr at room temperature in the dark. Next, the buffer was exchanged with 50 mM NH4HCO3 by washing the membrane three times. Free trypsin was added into the protein solution at a trypsin to protein ratio of 1:50 and incubated overnight at 37 ^o C. The tryptic digests were recovered in the supernatant after centrifugation, and an additional wash with water. The combined supernatants were vacuum- dried and then adjusted to 200 μL with 0.5% acetic acid. The peptide mixture was then subjected to C18 solid-phase extraction (The Nest Group, Ipswich, MA) for desalting, and subsequently vacuum-dried. In each case, 10 μg of peptides were used for the proteomic analysis, and 350 μg of peptides were subjected to phosphopeptide enrichment for phosphoproteomic analysis. Phosphopeptide enrichment [00208] Peptides were resuspended in 200 μL of phosphopeptide-binding buffer (20% lactic acid, 64% acetonitrile (ACN), 4% trifluoroacetic acid (TFA), 12%H2O), vortexed for 2 min, and incubated with 2 μg TiO ₂ beads (Titansphere, GL Sciences, Tokyo, Japan) for 30 min at room temperature. Next, the TiO2 beads were washed three times in wash buffer (80% ACN, 5% TFA, 15% H ₂ O), and phosphopeptides were eluted from the beads twice with 100 μL of 10% NH4OH, and once with 100 μL of elution buffer (10% NH4OH in water/100% ACN: 60/40, v/v). The elution was then subjected to desalting, dried by vacuum centrifugation, and resuspended for LC-MS analysis. Mass spectrometry data acquisition [00209] Proteomics data were acquired via LC-MS/MS using an UltiMate 3000 UHPLC (Thermo Fisher Scientific), coupled in-line with an Orbitrap Fusion Lumos mass spectrometer (Thermo Fisher Scientific) with an ESI nanospray source. Mobile phase A was composed of 0.1% formic acid (FA) in water, and mobile phase B was composed of 0.1% FA in ACN. The total flow rate was 300 nL min ^-1 , and peptides were separated over a 57-min gradient from 4% to 25% buffer B (total run time 90 min per sample) on an Acclaim PepMap RSLC column (50cm x 75 μm). Survey (MS) scans were acquired in Orbitrap (FT) with automated gain control (AGC) target 8E5, maximum injection time 50 msec, and dynamic exclusion of 30 sec across the scan range of 375-1800 m/z. MS/MS spectra were acquired in data-dependent acquisition mode at top speed for 3 sec per cycle; the AGC target was set to 1E4 with maximum injection time of 35 msec. Ions were subjected to stepped-energy higher- energy collision dissociation (seHCD) fragmentation at a normalized collision energy (NCE) of 20±5 %. Phosphopeptides were reconstituted in 0.1% FA in water and analyzed using the same LC-MS/MS setup as utilized for proteomic analysis. The peptide separation was achieved over an 87-min gradient (buffer A: 0.1% FA in water; buffer B: 0.1% FA in ACN) at a flow rate of 300 nL/min (4–25% B). SeHCD fragmentation was performed at NCE 25±5 %. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD035841. Label-free quantification analysis [00210] The raw LC-MS/MS data files were analyzed using MaxQuant (version 1.5.2.8), with the spectra searched against the corresponding Uniprot database (updated on May 21st, 2018). For identification of peptides, mass tolerances were 20 ppm for initial precursor ions, and 0.5 Da for fragmented ions. Two missed cleavages in tryptic digests were allowed. The multiplicity was set to two for the samples labeled with ¹³ C ¹⁵ N -L-Lys and ¹³ C ¹⁵ N -L-Arg. Cysteine residues were set as static modifications. Oxidation of methionine was set as the variable modification. Filtering for the peptide identification was set at a 1% false discovery rate (FDR). In vitro PDE6 activity assay [00211] A fluorescence enzymatic activity assay measuring PDE6- dependent cGMP hydrolysis in the presence of PDE inhibitors or DMSO vehicle was performed and analyzed as described previously. Briefly, the PDE6-containing fraction was concentrated to 5 mg/mL then mixed at a 1:50 ratio of PDE6 fraction to buffer solution, prior to incubation with selective PDE inhibitors or controls at 30ºC in black 96-well chimney-style UV- Star UV- Transparent Microplates (Greiner Bio-One, Monroe, NC) for 10 min in the Flexstation 3 Benchtop Microplate Reader (Molecular Devices, Sunnyvale, CA). PDE6-catalyzed cGMP hydrolysis was measured by fluorescence intensity recordings every 60 sec over 50 min at 30ºC. Data points were normalized as a percentage of the saturated value of the DMSO- vehicle reaction, and three technical replicates were used for each experimental condition. Quantitative Western blot analysis [00212] Fresh retinas were harvested from mice, and samples from both eyes of the same mouse were pooled and homogenized in RIPA buffer (Cell Signaling Technology, Danvers, MA), supplemented with a protease and phosphatase-inhibitor cocktail (Roche, Basel, Switzerland). Proteins were size-fractionated on 4-12% Bis-Tris Nu-PAGE gels (Invitrogen, Carlsbad, CA) and transferred to nitrocellulose membranes. The membranes were incubated in Intercept blocking solution (LI-COR, Lincoln, NE) for 1 hr at room temperature, followed by primary antibodies targeting RdCVF (1:500, #11203, Proteintech, Rosemont, IL), pCREB-S133 (1:1000, #0036R, Bioss, Woburn, MA), pCREB-S271 (1:1000, #CP4161, ECM Biosciences, Versailles, KY), or ICAM1 (1:1000, Proteintech #10020) in blocking buffer overnight at 4ºC. Membranes were washed with PBS containing 0.1% Tween-20 and incubated with an infrared dye (IR)-labeled goat anti-rabbit secondary antibody (1:3000, LI- COR #926-32211) for 1 hr at room temperature. Images of the blots were obtained and IR signals were quantified using a LI-COR Odyssey Fc imaging system. Immunofluorescence microscopy [00213] Mice were euthanized in a CO ₂ chamber prior to enucleation. Eyes were fixed in Hartman’s Fixative Solution (Sigma-Aldrich) overnight at room temperature and transferred to 30% sucrose in PBS for overnight incubation at 4°C, prior to embedding in OCT compound for cryosectioning and mounting onto glass slides (Superfrost Plus, Fisher Scientific). Slides were placed in blocking buffer containing 5% FBS, 1% BSA, and 0.2% Triton X-100 in PBS for 1 hr at room temperature for immunohistochemistry. Slides were then incubated with a primary antibody targeting TNFR1 (1:100, Bioss #2941R), Fas ligand (1:100, Bioss #0216R), PDE4D (1:100, Proteintech #12918), and/or biotinylated PNA (1:250; Vector Labs, Burlingame, CA) in blocking buffer overnight at 4°C, followed by a 0.5 hr incubation with fluorescent goat anti-rabbit secondary antibody (1:250, Invitrogen #A11037) and Alexa Fluor 488 streptavidin (1:250, Invitrogen, Carlsbad, CA) in blocking buffer at room temperature. Fluorescence microscopy images were obtained on a Keyence BZ-X810 fluorescent microscope (Keyence, Itasca, IL). Hallmarks of diabetic retinopathy analyses [00214] WT C57Bl/6J male mice (2-3 months of age) from the Jackson Laboratory were randomly assigned to the nondiabetic, diabetic, or rolipram-treated diabetic groups. Following induction of diabetes by streptozotocin, animals were euthanized for retinal phenotype characterization after 2 months of diabetes (5 months of age) to measure oxidative stress, inflammation, and leukocyte-mediated endothelial cell death; or after 8 months of diabetes (10 months of age) to measure capillary degeneration. Superoxide levels were measured chemically with lucigenin (bis-N-methylacridinium nitrate). Freshly isolated retinas were incubated in 200 ml of Krebs-Hepes buffer (pH 7.2) with 5 or 30 mM glucose for 7 min in 37°C in 5% CO ₂ . Luminescence indicating the presence of superoxide was measured 7 min after addition of lucigenin, with intensity recorded in arbitrary units per mg of protein. Leukocyte-mediated endothelial cytotoxicity was assessed as previously described. Briefly, mouse retinal endothelial cells (mRECs) (Cells Biologics, Chicago, IL) were grown in Dulbecco’s modified Eagle’s medium containing 10% FBS and 5.5 or 25 mmol/L glucose. When mRECs were 80% confluent (~500,000 cells), leukocytes (~100,000 cells) purified from blood with red blood cell lysis buffer were added and incubated for 24 h. After 24 h, mRECs were gently rinsed with PBS to remove non-adherent leukocytes, incubated with trypsin for 2 min, and washed twice in PBS. The viability of mRECs was determined by trypan blue exclusion with a hemocytometer. To assess retinal capillary degeneration, mouse eyes were fixed in formalin, and one retina from each animal was isolated, washed in running water overnight, and digested for 2 h in elastase. Following complete removal of neural cells, the isolated vasculature was laid out on a glass microscope slide, dried overnight, stained with hematoxylin and periodic acid-Schiff, dehydrated, and mounted with a glass coverslip. Degenerated (acellular) capillaries were quantitated in 6-7 field areas corresponding to the mid-retina (200 x magnification) in a masked manner. Acellular capillaries reported per square millimeter of retinal area were identified as capillary-sized vessel tubes having no nuclei along their length. Statistics [00215] Results were collected from at least five mice (n ≥ 5) per experimental group, unless otherwise indicated. Data were presented as mean ± standard error of the mean (SEM). Statistical significance between experimental groups was determined by the two- tailed Student’s t test, two- way analysis of variance (ANOVA), or as otherwise indicated, where a P value of less than 0.05 was considered statistically significant. Error bars represent SEM. Results Phosphodiesterases involved in regulating retinal homeostasis [00216] Our initial focus was delineating molecular mechanisms governed by PDEs in the retina. First, we determined by single-cell RNA-sequencing (scRNA-seq) that all PDE subtypes and isoforms are expressed across the various cell types of the murine retina (Fig.1B), indicating probable involvement of PDEs in regulating retinal homeostasis. Indeed, PDE6 isoforms exhibited high expression in rods and cones, consistent with the fundamental role of PDE6 in mediating visual phototransduction in photoreceptors via cGMP hydrolysis. Additionally, in the photosensitive dKO model of stress-inducible photoreceptor degeneration, we observed significant differential expression of most PDE isoforms in the retina 24 hours after exposure to bright-light stress (Fig.1C). Several PDEs became significantly upregulated with an average log2 fold-change (logFC) > 0.5 across many retinal cell types under stress, especially in photoreceptors, Müller glia, microglia, astrocytes, and horizontal cells (Fig.1D). Indeed, increased PDE4D expression throughout the retina was confirmed at the protein level by immunohistochemistry (Fig.9). Among the PDEs significantly upregulated under stress, PDE2, PDE4, and PDE11 can be inhibited selectively by the chemical compounds BAY 60-7550, rolipram, and BC11-38, respectively. Thus, we reasoned that if the increased PDE activity in these cell types drives the pathogenesis of stress-induced retinal degeneration, then targeted pharmacological inhibition of these select PDEs would mitigate light damage in photosensitive dKO mice. Pathways regulated by stress and phosphodiesterases in ARPE-19 cells [00217] The light-sensitive dKO model has the Abca4 ^-/- Rdh8 ^-/- genotype that phenotypically predisposes to accumulation of all-trans-retinal (atRAL) and associated cytotoxic adducts due to visual cycle deficiencies, and these toxic reactions are accelerated during exposure to bright-light stress. To delineate the molecular mechanisms underlying atRAL-induced toxicity, we first employed an in vitro fluorescence assay of Ca ²⁺ -associated cytotoxicity, using the human- derived ARPE-19 cell line. This approach is based on previous studies investigating atRAL exposure and apoptotic cell death, in the context of aberrant ionic gradients and intracellular Ca ²⁺ elevation. In ARPE-19 cells exposed to 60 μM atRAL stress, we observed significantly increased intracellular Ca ²⁺ by Fluo-3 AM staining relative to DMSO-treated controls, consistent with Ca ²⁺ -associated cytotoxicity (Fig.2). In ARPE-19 cells treated with 10 μM BAY 60-7550, rolipram, or BC11-38 this atRAL-induced Ca ²⁺ elevation was reduced by approximately 50%, suggesting that selective inhibition of PDE2, PDE4, or PDE11 confers protection against atRAL- induced cytotoxicity. [00218] To obtain an unbiased, thorough understanding of the biological pathways implicated in atRAL-induced cytotoxicity and PDE-inhibitor-mediated cytoprotection, we performed a mass spectrometry-based quantitative proteomic analysis of ARPE-19 cells, using stable-isotope labeling of amino acids in cell culture (SILAC). We identified differentially expressed proteins in ARPE-19 cells exposed to stress (60 μM atRAL or 5 mM H2O2) in the absence or presence of PDE inhibitor (10 μM BAY 60-7550, rolipram, or BC11- 38), relative to vehicle-treated controls. From the lists of differentially expressed proteins, we filtered for those that were upregulated by both atRAL and oxidative stress and downregulated by all three PDE inhibitors; and conversely, those that were downregulated by both types of stress and upregulated by all three PDE inhibitors. This selection allowed us to focus on universal mechanisms of stress-induced cytotoxicity and PDE-inhibitor-mediated cytoprotection. The protein networks so identified were mapped according to functional enrichments (Fig.10A), which revealed biological pathways of significance involving cellular response to stress, protein homeostasis, chromatin remodeling, immune regulation, post-translational modifications, and JAK-STAT signaling (Fig.10B). Individual proteins implicated in these pathways were differentially expressed under stress and with PDE- inhibitor treatment, and the degree of differential expression was quantified by logFC (Fig.10C). [00219] Through the quantitative proteomics analysis of ARPE-19 cells, we identified mitochondrial apoptosis-inducing factor 1 (AIFM1) and endoplasmic reticulum calcium ATPase 2 (ATP2A2), both of which were upregulated under stress yet downregulated by PDE-inhibitor treatment, consistent with their previously described functions in driving apoptosis through Ca ²⁺ - mediated signaling. We also identified additional proteins implicated in various homeostatic processes, including stress-induced apoptosis, phagocytosis of apoptotic cells, signaling networks mediated by TNF or Ca ²⁺ , histone modifications, DNA damage repair, autophagy, chaperone-mediated refolding, or the ubiquitin-proteasome system (Table 1). Altogether, these in vitro studies support the conclusion that stress-induced cytotoxicity involves apoptosis driven by TNF- and Ca ²⁺ -mediated signaling pathways, suggesting that PDE inhibition promotes resilience to stress in part through suppression of these apoptotic processes. Table 1 - list of all proteins in ARPE-19 cells, either upregulated by both atRAL and oxidative stress and downregulated by all three PDE inhibitors (BAY 60-7550, rolipram, and BC 11-38), or downregulated by both types of stress and upregulated by all three PDE inhibitors ACADL CDK1 EIF4G1 LRRC59 PSME2 SNRNP70 ACO2 CGI-74 FERMT2 MARS PXN SNRPA1 [00220] Having demonstrated in vitro attenuation of atRAL-induced cytotoxicity in human ARPE- 19 cells by PDE-inhibitor treatment, we next investigated the effects of selective PDE-inhibitor therapy in vivo, using our photosensitive dKO model. These mice were administered BAY 60- 7550, rolipram, or BC11-38 by intraperitoneal injection (2 mg/kg) 30 min prior to bright-light stress exposure, and their retinal phenotypes were characterized 1 week later. Scanning Laser Ophthalmoscopy (SLO) and Optical Coherence Tomography (OCT) were utilized to obtain images of the fundus and retinal cross-sections, respectively (Fig.3A). In vehicle-treated dKO mice exposed to stress, SLO imaging revealed characteristic autofluorescent puncta associated with phototoxicity and reactive inflammation, while OCT imaging revealed concomitant degeneration of the photoreceptor- containing outer nuclear layer (ONL), relative to WT and unstressed controls (Fig.3B). Moreover, scotopic electroretinogram (ERG) recordings from these mice revealed significantly diminished average a-wave and b-wave amplitudes relative to unstressed controls, indicating impairment of outer and inner retinal function, respectively, concomitant with structural degeneration (Fig.3C). However, in dKO mice treated with selective inhibitors of PDE2, PDE4, or PDE11 both retinal structure and function were protected from the degenerative effects induced by stress, thus demonstrating the efficacy of PDE-inhibitor therapy in vivo. [00221] To rule out the possibility that protective effects conferred by selective PDE- inhibitor therapy could be confounded by off-target nonselective inhibition of PDE6- dependent phototransduction, we first performed a fluorescence enzymatic activity assay of PDE6-catalyzed cGMP hydrolysis using bovine ROS in vitro. With the nonselective PDE inhibitor vardenafil as a positive control, we observed an approximate two-fold reduction in PDE6 activity at a vardenafil concentration of 1 μM, relative to the DMSO negative control group (Fig.11. In contrast, the selective PDE inhibitors tested at the same drug concentration did not exhibit substantial impairment of PDE6 activity, suggesting that the observed protective effects conferred by selective PDE inhibition are independent of any potential off- target inhibitory effects on PDE6 and/or phototransduction. To confirm this interpretation in vivo, we performed scotopic ERG analyses on unstressed dKO mice 30 min after intraperitoneal administration of 2 mg/kg PDE inhibitor (BAY 60-7550, rolipram, BC11-38, or vardenafil) or DMSO vehicle. While vardenafil- treated mice exhibited a significant decrease in both a-wave and b-wave amplitudes, mice treated with selective inhibitors of PDE2, PDE4, or PDE11 displayed ERG amplitudes within the range of vehicle-treated controls (Fig.12). Taken together, these in vitro and in vivo analyses indicate that visual phototransduction is not substantially impaired by the selective PDE inhibitors, therefore supporting the potential clinical feasibility of this therapeutic approach for preserving vision in degenerative blinding diseases. Molecular mechanisms of stress resilience and phosphodiesterase inhibitor therapy [00222] After ruling out the phototransduction pathway as a potential confounder, we performed scRNA-seq analyses on photosensitive dKO mice to identify molecular mechanisms responsible for the therapeutic effects of selective PDE inhibition, focusing on the PDE4- and PDE11-selective inhibitors that yielded the most significant improvement in photoreceptor viability. We first utilized Uniform Manifold Approximation and Projection (UMAP) dimensionality reduction to generate a visual representation of transcriptomic differences between individual retinal cells. In a two-dimensional UMAP, the degree of difference between individual transcriptomic profiles is directly proportional to the distance between corresponding points, which segregate into distinct clusters that can be assigned according to cell type (Fig.4A). Through a UMAP comparison highlighting retinal cells from unstressed versus stressed dKO mice, we identified certain clusters in which the effect of stress on transcriptomic changes was especially pronounced; namely, in the photoreceptors, Müller glia, astrocytes, and other glia (Fig.4B). However, in the PDE- inhibitor-treated groups, these stress-induced transcriptomic shifts were largely attenuated, and their respective transcriptomic profiles generally resembled that of the unstressed controls. Among the most significant differentially expressed genes in the clusters of interest, we identified glutamine synthetase (Glul), which was broadly downregulated with stress, especially in Müller glia, microglia, astrocytes, and retinal pigment epithelium (RPE) (Fig.4C). Notably, the PDE-inhibitor-treated groups exhibited converse upregulation of Glul to levels surpassing those of unstressed dKO mice, suggesting that PDE-inhibitor therapy stimulates mechanisms of somatic maintenance to levels that support enhanced resilience to stress. Indeed, Glul has been implicated in the catalytic conversion of neurotoxic glutamate or ammonia to nontoxic glutamine, consistent with a neuroprotective role in somatic maintenance. [00223] In contrast, we also identified tumor necrosis factor receptor superfamily member 12A (Tnfrsf12a), a known inducer of apoptosis, which became significantly upregulated with stress, especially in cones, horizontal cells, Müller glia, microglia, astrocytes, and RPE (Fig.4D). PDE-inhibitor therapy broadly mitigated stress-induced upregulation of Tnfrsf12a across most retinal cell types, and in some cases even suppressed expression to levels below that of unstressed controls, suggesting that the enhanced stress- resilience phenotype is enabled by a synergistic combination of anti-apoptotic effects and improved somatic maintenance, conferred by selective PDE inhibition. In further support of this interpretation, many of the additional genes we identified, which exhibited reduced expression in relevant cell types under stress but were upregulated by PDE-inhibitor therapy, are involved in somatic maintenance; and other genes, which became upregulated under stress but were attenuated by selective PDE inhibition, are implicated in driving apoptosis and/or cell death (Table 2). Table 2 - List of all differentially expressed genes (statistically significant, adjusted P value < 0.05) identified by scRNA-seq in dKO murine retina, either upregulated 1 day after exposure to bright-light stress and downregulated by both rolipram and BC11-38, or downregulated by stress and upregulated by both PDE inhibitors A2m Capns1 Ddx18 Gdf15 Hsp90aa1 Mdk Opn1mw Rasgrf2 Slc25a5 Trhde Ab 5 C r14 Dd 39 Gf H 4l Md 1 O 1 Rb 17 Sl 2 1 Trib3 7 1a 1 1 d3 d4 13 4 1c 2a 6 1 2 1 3b 3c 10 Ahnak2 Cers2 Egr2 Gm42697 Itga4 mt-Nd4 Pde6g Rpl36al Spc25 Usp2 Ahr Cers4 Ehd1 Gm45159 Jagn1 mt-Nd4l Pdlim7 Rplp2 Spred1 Usp33 2 a c1 r 1 a 3 c b c7 6 7 28 5 2 38 ik 0 ^5I k 37I k 58I k Fam43 B2m Cox17 _{Guca1a Lmo1 Nme1 Prmt1 Serping1 Tcf7l2} ^4933429 a O19Rik next sought to verify these processes in photosensitive dKO mice at the protein level, using combined label- free mass spectrometry-based quantitative proteomic and phosphoproteomic analyses. First, we identified differentially expressed proteins in retinas exposed to bright- light stress relative to unstressed controls. Next, we identified differentially expressed proteins in PDE-inhibitor-treated mice exposed to stress relative to vehicle-treated controls. From these lists of differentially expressed proteins, we filtered for those that were both upregulated by stress and downregulated by PDE-inhibitor therapy, and conversely for those that were both downregulated by stress and upregulated by PDE-inhibitor therapy. This selection process allowed us to focus on universal mechanisms of stress-induced retinal degeneration and PDE-inhibitor-mediated protection. The protein networks so identified were mapped according to functional enrichments, which revealed biological pathways of significance involving cellular response to stress, protein and/or mitochondrial homeostasis, chromatin remodeling, inflammatory response, post-translational modifications, apoptosis, and signaling by mTOR, JAK-STAT, or second messengers (Figs.13A-C). Individual proteins within these functional pathways became differentially expressed under stress and with PDE-inhibitor treatment, and the degree of differential expression was quantified by logFC (Fig.5A). [00225] Through the quantitative proteomics analysis of dKO mice, we identified mitochondrial calcium uniporter protein (MCU) and growth hormone-inducible transmembrane protein (GHITM), both of which were downregulated by stress yet upregulated by PDE-inhibitor treatment, consistent with their previously described functions in mediating apoptosis through regulation of mitochondrial Ca ²⁺ uptake in response to stress. This analysis also revealed additional proteins of interest involved in promoting cell survival or apoptosis in response to stress, TNF or Ca ²⁺ -mediated signaling, histone modifications, DNA damage repair, antioxidant defense, autophagy, chaperone-mediated refolding, or the ubiquitin-proteasome system (Table 3). Notably, histone deacetylase 11 (HDAC11) and complement C3 (C3), both of which were upregulated by stress but attenuated by PDE- inhibitor therapy, have also been implicated in the pathogenesis of human AMD, demonstrating commonality in the mechanisms driving retinal degeneration between the photosensitive dKO model and human subjects with AMD. Moreover, rod-derived cone viability factor (RdCVF), also known as nucleoredoxin-like protein 1 (NXNL1), a somatic maintenance protein that promotes cone photoreceptor survival, was depleted by stress but partially restored with PDE-inhibitor therapy, and this finding was validated through traditional quantitative Western blot analysis (Fig.5B). Table 3 - list of all proteins in dKO either upregulated 1 day after exposure to bright-light stress and downregulated by all three PDE inhibitors (BAY 60-7550, rolipram, and BC 11-38), or downregulated by stress and upregulated by all three PDE inhibitors. n = 3-6 per group AARS CLIC6 GAPDH MPP6 PRPS1 SEPT8 ABHD12 CLTA GDI2 MSI2 PRPSAP2 SERBP1 D APOA1 DHX15 HNRNPL PADI2 RBP1 SV2B APPL1 DHX9 HNRNPU PAICS RCC1 SYN1 CEND1 FHL1 MDH1 PRKCA SEPT5 YWHAG CENPV FIS1 MPC2 PRMT5 SEPT6 ZFP385A p ertinent post-translational modifications in the context of phosphorylation-mediated signaling pathways associated with retinal degeneration or protection (Fig.5C). As would be expected with PDE inhibition increasing intracellular cyclic nucleotide concentration and inducing PKA-dependent phosphorylation of downstream targets, we detected increased phosphorylation of cAMP- responsive element-binding protein 1 (CREB1) in PDE-inhibitor- treated dKO mice compared to vehicle-treated controls. This apparent protection from stress- induced CREB1 hypophosphorylation, in PDE-inhibitor-treated mice, was confirmed by quantitative Western blot analysis, both at the canonical serine 133 phospho-site (S133) and at serine 271 (S271) (Fig.13D). Therefore, these results exemplify how PDE-inhibitor therapy could attenuate stress-induced phosphoproteomic dysregulation and promote resilience to stress, in part through phosphorylation-mediated second messenger signaling pathways. Indeed, reduced phosphorylation and activity of CREB1 have generally been associated with neurodegenerative processes promoting apoptosis, whereas increased phosphorylation and activity of CREB1 have been associated with neuroprotective processes promoting somatic maintenance and survival. [00227] Altogether, these transcriptomic, proteomic, and phosphoproteomic analyses support the hypothesis that selective PDE inhibition enhances resilience to stress in the retina, both by promoting somatic maintenance and by inhibiting apoptosis via cyclic nucleotide- mediated second messenger signaling pathways. To validate these findings and gain insights into the time course of pertinent protective and/or degenerative processes, we conducted a bulk RNA-seq analysis of whole dKO retinas collected at 6 hours, 1 day, and 3 days after exposure to stress. We confirmed significant time-dependent decreases in expression of Glul, Nxnl1, Xiap, and Tulp1, consistent with stress-induced depletion of somatic maintenance processes (Fig.6A). Conversely, we also confirmed time-dependent upregulation of Tnfrsf12a and C3, consistent with stress-induced apoptosis and complement activation, respectively (Fig.6B). In further support of the anti-apoptotic effects conferred by PDE- inhibitor therapy, our bulk RNA-seq analysis revealed that both the intrinsic and extrinsic canonical apoptotic pathways, driven by Trp53, Fas, and Tnfrsf1a, are significantly upregulated at different time points after exposure to stress, relative to unstressed controls. To corroborate this transcriptional upregulation of apoptotic processes at the protein level, we utilized immunohistochemistry to visualize TNFR1 expression in retinal cross-sections prepared from dKO mice. Peanut agglutinin (PNA) staining revealed photoreceptor degeneration, particularly in the outer segment (OS) layer in vehicle-treated dKO mice 1 day after exposure to stress, relative to unstressed controls (Fig.6C); this OS degeneration was accompanied by widespread upregulation of TNFR1. Rolipram therapy attenuated TNFR1 upregulation while protecting photosensitive dKO mice from acute stress-induced photoreceptor degeneration. Conserved retinal protection across models of acute and chronic stress [00228] We next questioned whether the therapeutic effect of selective PDE inhibition is limited to the photosensitive dKO model of acute stress, or if protection could be similarly conferred in models of chronic retinal degeneration. To investigate this possibility, we first employed the rd10 mouse model of autosomal recessive retinitis pigmentosa, which exhibits progressive photoreceptor degeneration under standard lighting conditions. Over the course of two weeks, rd10 mice were reared under standard lighting, on either a control (base) diet or a rolipram- infused rodent chow diet, and their retinal phenotypes were characterized at the end of the two- week period. Through OCT and SLO imaging, rd10 mice on the rolipram diet exhibited protection from retinal degeneration, as well as attenuation of autofluorescent puncta associated with phototoxicity and reactive inflammation, compared to rd10 mice on the control diet (Fig.14). In addition, immunohistochemistry studies demonstrated reduced extrinsic apoptosis with PDE-inhibitor therapy; Fas signaling was largely attenuated by the rolipram diet (Fig.7A), accompanied by significant improvement of photoreceptor viability (Fig.7B). Consistent with retinal structure preservation in rd10 mice on the rolipram diet, photopic ERG analyses revealed improvement in retinal function as well (Fig.7B). Moreover, in another murine model of chronic retinal degeneration, the streptozotocin model of diabetic retinopathy, rolipram therapy alleviated the hallmarks of chronic disease in a dose-dependent manner, resulting in significant reduction of retinal oxidative stress and inflammation (Fig.7D-E), as well as protection from leukocyte- mediated endothelial cell death (Fig.7F) and retinal capillary degeneration (Fig.7G). Taken together, these data indicate that the molecular mechanisms promoting stress resilience, which are enhanced by PDE-inhibitor therapy, may be broadly responsive across various retinopathies involving acute and/or chronic stressors. [00229] A paradox arises when we consider the results of the current study of selective PDE- inhibitor therapy and previous studies of GPCR-targeted Metoprolol-Bromocriptine- Tamsulosin (MBT) combination therapy. Whereas PDE inhibition increases intracellular cyclic nucleotide concentrations, MBT therapy reduces second messenger availability; thus, two therapeutic approaches would be expected to yield opposing outcomes. However, both PDE-inhibitor and MBT therapies confer protection against retinal degeneration. There are several potential scenarios that could underlie this apparent paradox. First, the retina is a complex tissue comprised of multiple cell types, so drug targets could be differentially expressed across the distinct cell types. Accordingly, there may be no substantial contradictory action between the two treatments on intracellular cyclic nucleotide concentrations in a given cell type. For example, if the retinal cell types expressing PDE11 do not express the GPCRs targeted by MBT therapy, and vice versa, then either increased cyclic nucleotide concentration in the PDE11-expressing cell types or decreased cyclic nucleotide concentration in the GPCR-expressing cell types could produce a similar end result, with intercellular communication between the distinct retinal cell types converging on a common physiological response at the tissue level. Secondly, a recent discovery revealed that GPCRs likely signal via subcellular microenvironments with highly localized concentrations of cAMP, known as receptor-associated independent cAMP nanodomains (RAINs), corresponding to thousands of self-sufficient, independent signaling units. Thus, the distribution of RAINs could also account for the apparent therapeutic paradox, as any single cell could contain RAINs modulated by MBT therapy which are distinct and separate from the cyclic nucleotide microenvironments modulated by selective PDE-inhibitor therapy. In the context of a systems pharmacology paradigm that also considers the phenomenon of biased agonism, it becomes less challenging to rationalize how integration of differential effects on cyclic nucleotide concentrations in different cell types or microenvironments within the retina could culminate in a common stress-resilient retinal phenotype. [00230] Given that the billions of cells that make up the retina and brain and the trillions of cells comprising the rest of the human body are all derived from a common eukaryotic ancestor, it is certainly possible, if not probable, that at least some vital somatic maintenance and pathological processes are common to various degenerative diseases of distinct etiologies, as well as across humans, mammals, and murine disease models. While it is important to acknowledge certain limitations, the intrinsic advantages of employing highly tractable animal models that recapitulate hallmarks of human retinopathies cannot be overstated. For instance, although it may be fundamentally impossible to replicate the chronic, multifactorial pathogenesis of human AMD in the mouse with no cone-enriched macula, it is nevertheless reasonable to employ the dKO model as an acute, stress-inducible surrogate that effectively recapitulates epigenetic hallmarks such as reduced global chromatin accessibility; as well as other major pathological features of AMD, including photoreceptor degeneration, lipofuscin accumulation, drusen deposition, and late-onset choroidal neovascularization. The fundamental goal in using murine models for this study was to identify universal molecular mechanisms of degeneration and protection, thereby revealing novel drug targets and pharmacological interventions, such as the selective PDE inhibitors described herein, with potential clinical utility to treat both age-related and inherited retinal degenerations causing blindness. [00231] Despite the seemingly disparate pathological mechanisms underlying the vast array of age-related diseases, a common underlying thread across every disease manifesting in advanced age is the loss of resilience to stress. This theory of human aging has been confirmed independently across distinct academic disciplines, from mathematics and statistics to physiology and medicine. It is, therefore, conceivable that chronic degenerative disorders, such as those associated with aging, could be treated with drugs intentionally designed to enhance physiological resilience to stress. Example 2 Intraocular pressure (IOP) stress induction [00232] Male and female wild-type (WT) mice aged at least 12 months on the C57BL/6J genetic background were housed at the University of California, Irvine (UCI) and reared for at least 1 week on either a base diet of rodent chow (LabDiet Prolab RMH3000) or the base chow infused with rolipram at a concentration of 100 ppm (LabDiet 5GAT). These mice were age- and litter-matched with control mice for all experiments, and body weights were recorded twice per week to confirm that feeding behavior was not affected by the difference between the two diets. IOP stress was induced by subjecting each mouse to unilateral hydrostatic pressure-induced IOP elevation to 40 mm Hg for 30 min, with the contralateral eye as the negative (unstressed) control. At 5-7 days following IOP stress induction, retinal ganglion cell (RGC) function was assessed by pattern electroretinography (pERG), and RGC density was quantified by immunohistochemistry. Pattern electroretinography (pERG) [00233] All mice were dark-adapted for at least 12 h prior to pERG recordings, which were obtained using the Celeris ERG platform equipped with pattern ERG stimulators (Diagnosys LLC). All mice were anesthetized by intraperitoneally administered Ketamine and Xylazine (100 mg/kg and 10 mg/kg, respectively). For electrode placement on corneal surfaces, eyes were anesthetized with topical ophthalmic proparacaine (0.5%, Bausch-Lomb), dilated with topical ophthalmic phenylephrine (2.5%, Akorn Pharmaceuticals) and tropicamide (1%, Alcon Laboratories), and lubricated with corneal gel. For all mice, 400 sweeps (reads) per eye were recorded and averaged. pERG values were measured between first positive peak (P1) and second negative peak (N2) amplitudes. Immunohistochemistry (IHC) for RGC counts [00234] Mice were euthanized in a CO2 chamber prior to enucleation. For IHC staining of retina flat mounts, the cornea and lens were first dissected out, then the remaining neural retina was separated from the RPE-containing posterior eye cup and fixed in 4% paraformaldehyde for 2 h. Retinal eye cups were then flattened by making long radial cuts and mounted on glass slides (Superfrost Plus Gold, Fisher Scientific). For flat mount IHC staining, slides were incubated in a blocking buffer containing 10% bovine serum albumin (BSA) and 0.5% Triton X-100 in PBS for 1 h at RT. Slides were then incubated with a primary antibody targeting RBPMS (1:100, Sigma-Aldrich #ABN1362) overnight at 4°C, followed by a 1 h incubation with a fluorescent goat anti-rabbit secondary antibody (1:250, Invitrogen #A11037). Fluorescence microscopy images were obtained on a Keyence BZ- X810 fluorescent microscope, and RGC density was averaged per mm ² from total cell counts in representative 0.5 mm x 0.5 mm image sections. Results [00235] Fig.15 illustrates a graph showing protection of retina against 10,000 lux 30 minute lights induced degeneration in Abca ^-/- Rdh8 ^-/- double knock out mice by various selective PDE inhibitors. PDE inhibitor therapy in glaucoma (IOP stressed mouse) model [00236] Fig.16 illustrates pERG traces of control eyes of mice reared on a base or rolipram-infused diet for one week prior to initiating IOP stress (40 mm Hg for 30 min) followed by pERG recordings 5-7 days after stress. [00237] Fig.17 illustrates pERG traces of IOP eyes of mice reared on a base or rolipram-infused diet for one week prior to initiating intraocular pressure (IOP) stress followed by pERG recordings 5-7 days after stress. [00238] Fig.18 illustrates images of retinal ganglion cell in IOP eyes of mice reared on base or rolipram infused diet. [00239] Fig.19 illustrates retinal ganglion cell density in IOP eyes of mice reared on base or rolipram infused diet. [00240] Fig.20 illustrates graphs summarizing pERG Averages of IOP eyes of mice reared on a base or rolipram-infused diet for one week prior to initiating intraocular pressure (IOP) stress followed by pERG recordings 5-7 days after stress. [00241] From the above description of the invention, those skilled in the art will perceive improvements, changes and modifications. Such improvements, changes and modifications within the skill of the art are intended to be covered by the appended claims. All references, publications, and patents cited in the present application are herein incorporated by reference in their entirety.