An interdisciplinary consortium of investigators from the Departments of Medicine, Pharmacology, Ophthalmology, Pediatrics and Biomedical Engineering at Case Western Reserve University, in collaboration with the University of Michigan, Harvard University, and Boston University proposes to increase the pace at which basic science discoveries on disease mechanisms can be translated into therapies for complex visual system disorders and disease, a stated goal of the R24 National Eye Institute (NEI) Translational Research Program on Therapy for Visual Disorders. This scientific partnership will employ its diverse scientific expertise to characterize and test potential therapies for diabetic and other ischemic retinopathies in animal models by using a combination of cutting-edge physiological, chemical, analytical and imaging approaches. By identifying drugs with the capability to inhibit clinically important lesions of the early stages of diabetic retinopathy in animal models, we will accelerate their development before testing in humans. Improving drug delivery to the retina will also be a high priority. Conventional and emerging technologies together with high resolution imaging methods will be used noninvasively to assess various processes in the retina, and document the effect of therapies. Specific goals of this project are to: 1. Use retinylamine as the lead compound to develop and test the ability of other amino-containing compounds (derivatives from chemical libraries and chemicals synthesized especially for this project) to trap reactive aldehydes and/or inhibit superoxide generation by retinal cells incubated in glucose concentrations similar to those found in diabetes. A systems pharmacology approach will be employed to evaluate the ability of a second group of compounds consisting of agonists and antagonists of G protein-coupled receptors (GPCRs) to achieve similar therapeutic effects. 2. Test the best of these compounds singly and in combination for their ability to (a) inhibit lesions of the non-proliferative stage of diabetic retinopathy (increased capillary permeability and degeneration) in rodents and primates, and (b) inhibit capillary dropout and pre-retinal neovascularization in the oxygen- induced retinopathy model. 3. Assess the retention and efficacy of promising test drugs delivered to the retina by different routes compared to systemic delivery. An important criterion for selection of compounds for further study is that they do not impair visual function at the doses used. Ultimately, results of these interrelated aims will guide us in identifying the most promising therapeutics for further development in reducing retinopathy and vision loss in diabetic individuals.

Public Health Relevance

Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults of industrialized nations. Good glycemic control can inhibit DR in motivated patients, but is difficult or impossible for many to achieve and maintain. Likewise, other therapies (such as fibrates) seem to inhibit DR progression, but only in a subgroup of diabetic individuals. Thus, additional therapeutic approaches are needed to reduce vision loss in diabetes. The goal of this application is to identify novel, effective, and safe therapeutics that slow or halt the development and progression of DR in animal models as a prelude to clinical studies.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Resource-Related Research Projects (R24)
Project #
5R24EY024864-04
Application #
9472329
Study Section
Special Emphasis Panel (ZEY1)
Program Officer
Agarwal, Neeraj
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Joyal, Jean-S├ębastien; Gantner, Marin L; Smith, Lois E H (2017) Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism. Prog Retin Eye Res :
Gong, Yan; Fu, Zhongjie; Liegl, Raffael et al. (2017) ?-3 and ?-6 long-chain PUFAs and their enzymatic metabolites in neovascular eye diseases. Am J Clin Nutr 106:16-26
Chen, Jiahuan; Fu, Yi; Day, Daniel S et al. (2017) VEGF amplifies transcription through ETS1 acetylation to enable angiogenesis. Nat Commun 8:383
Sun, Ye; Lin, Zhiqiang; Liu, Chi-Hsiu et al. (2017) Inflammatory signals from photoreceptor modulate pathological retinal angiogenesis via c-Fos. J Exp Med 214:1753-1767
Sun, Ye; Liegl, Raffael; Gong, Yan et al. (2017) Sema3f Protects Against Subretinal Neovascularization In Vivo. EBioMedicine 18:281-287
Alexander, Nathan S; Katayama, Kota; Sun, Wenyu et al. (2017) Complex binding pathways determine the regeneration of mammalian green cone opsin with a locked retinal analogue. J Biol Chem 292:10983-10997
Levin, Leonard A; Miller, Joan W; Zack, Donald J et al. (2017) Special Commentary: Early Clinical Development of Cell Replacement Therapy: Considerations for the National Eye Institute Audacious Goals Initiative. Ophthalmology 124:926-934
Jastrzebska, Beata; Comar, William D; Kaliszewski, Megan J et al. (2017) A G Protein-Coupled Receptor Dimerization Interface in Human Cone Opsins. Biochemistry 56:61-72
Cheng, Yan; Du, Yunpeng; Liu, Haitao et al. (2017) Photobiodulation Inhibits Long-Term Structural and Functional Lesions of Diabetic Retinopathy. Diabetes :
Chiang, Cheng-Kang; Tworak, Aleksander; Kevany, Brian M et al. (2017) Quantitative phosphoproteomics reveals involvement of multiple signaling pathways in early phagocytosis by the retinal pigmented epithelium. J Biol Chem 292:19826-19839

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