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 #
1R24EY024864-01
Application #
8792272
Study Section
Special Emphasis Panel (ZEY1)
Program Officer
Agarwal, Neeraj
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
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
Choi, Elliot H; Suh, Susie; Sander, Christopher L et al. (2018) Insights into the pathogenesis of dominant retinitis pigmentosa associated with a D477G mutation in RPE65. Hum Mol Genet 27:2225-2243
Orban, Tivadar; Leinonen, Henri; Getter, Tamar et al. (2018) A Combination of G Protein-Coupled Receptor Modulators Protects Photoreceptors from Degeneration. J Pharmacol Exp Ther 364:207-220
Sun, Ye; Smith, Lois E H (2018) Retinal Vasculature in Development and Diseases. Annu Rev Vis Sci 4:101-122
Cakir, Bertan; Liegl, Raffael; Hellgren, Gunnel et al. (2018) Thrombocytopenia is associated with severe retinopathy of prematurity. JCI Insight 3:
Nahomi, Rooban B; Sampathkumar, Sruthi; Myers, Angela M et al. (2018) The Absence of Indoleamine 2,3-Dioxygenase Inhibits Retinal Capillary Degeneration in Diabetic Mice. Invest Ophthalmol Vis Sci 59:2042-2053
Kiser, Philip D; Zhang, Jianye; Sharma, Aditya et al. (2018) Retinoid isomerase inhibitors impair but do not block mammalian cone photoreceptor function. J Gen Physiol 150:571-590
Nilsson, Anders K; Löfqvist, Chatarina; Najm, Svetlana et al. (2018) Influence of Human Milk and Parenteral Lipid Emulsions on Serum Fatty Acid Profiles in Extremely Preterm Infants. JPEN J Parenter Enteral Nutr :
Luu, Jennings; Palczewski, Krzysztof (2018) Human aging and disease: Lessons from age-related macular degeneration. Proc Natl Acad Sci U S A 115:2866-2872
Gao, Songqi; Parmar, Tanu; Palczewska, Grazyna et al. (2018) Protective Effect of a Locked Retinal Chromophore Analog against Light-Induced Retinal Degeneration. Mol Pharmacol 94:1132-1144
Fu, Zhongjie; Löfqvist, Chatarina A; Liegl, Raffael et al. (2018) Photoreceptor glucose metabolism determines normal retinal vascular growth. EMBO Mol Med 10:76-90

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