This project seeks to develop new therapies for diabetic retinopathy (DR) by targeting the anti-inflammatory G-protein coupled receptor, GPR109A. Inflammation is crucial in the pathogenesis of DR. However at present, clinical strategies for reducing diabetes-induced inflammation in retina are limited. As such, there is a great and urgent need for identification of new anti-inflammatory targets and strategies. GPR109A is the receptor for the lipid-lowering agent niacin. Other than its anti-lipolytic actions, it is noted functionally for eliciting potent anti-inflammatory effects in some cell types/tissue types, a phenomenon that has not been studied in retina. We published recently, the first report on GPR109A expression in RPE, and preliminary work in our lab demonstrates convincingly expression of the receptor also in microglia and endothelial cells. RPE, endothelial and microglial cells each have known roles in the regulation of immunity and inflammation in retina, and are critically affected in the pathogenesis of DR. Hence, we predict an anti-inflammatory role for GPR109A also in these cells. Evidence that atop is anti-inflammatory effects, GPR109A influences multiple other cellular processes including: maintenance of energy homeostasis, oxidative stress, lipid/cholesterol homeostasis and angiogenesis, actions that too would be highly desirable in diabetic retina, make GPR109A a highly attractive therapeutic target. Our hypothesis is therefore, that in retina, upon activation, GPR109A disrupts/inhibits pro-inflammatory, pro-oxidative and/or pro-angiogenic pathways at multiple points, thereby reducing inflammation and preventing the development and progression of DR. To test this hypothesis, we have developed and readily available for use in our laboratory, a number of innovative mouse model systems including the Gpr019a-knockout, primary cell culture systems for RPE, microglia and endothelial cells, and unique assay systems to monitor GPR109A activation by different agonists, pharmacologic and endogenous. To date, there have been no other investigations of GPR109A in retina. If the role of the receptor in processes related to the pathogenesis/progression of DR can be established (our present goal), the receptor would have considerable impact as a new and effective target for prevention and/or early intervention in this disease. The proposed study is significant in that it represents the first step in a continuum of research that is expected to lead to the development of effective pharmacologic strategies for modulation of GPR109A activity and thereby inflammation in retina.

Public Health Relevance

Inflammation has been implicated as a major causative factor in the development and progression of degenerative retinal diseases like diabetic retinopathy, the leading cause of blindness among adults in the U.S. As such, therapies effective at limiting inflammation may slow or prevent the progression of the disease. We discovered recently a receptor called GPR109A in retina, that when activated is predicted to do just that, reduce inflammation and prevent and/or treat retinal disease. The present studies will explore this phenomenon in greater detail; understanding the mechanisms regulating GPR109A and how to control it in diabetic conditions will contribute to the development of new, effective strategies fr not only the treatment and prevention of diabetic retinopathy, but of a number of retinal diseases in which inflammation is majorly involved.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Mckie, George Ann
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Augusta University
Schools of Medicine
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Jadeja, Ravirajsinh N; Powell, Folami L; Jones, Malita A et al. (2018) Loss of NAMPT in aging retinal pigment epithelium reduces NAD+ availability and promotes cellular senescence. Aging (Albany NY) 10:1306-1323
Thounaojam, Menaka C; Powell, Folami L; Patel, Sagar et al. (2017) Protective effects of agonists of growth hormone-releasing hormone (GHRH) in early experimental diabetic retinopathy. Proc Natl Acad Sci U S A 114:13248-13253
Promsote, Wanwisa; Powell, Folami Lamoke; Veean, Satyam et al. (2016) Oral Monomethyl Fumarate Therapy Ameliorates Retinopathy in a Humanized Mouse Model of Sickle Cell Disease. Antioxid Redox Signal 25:921-935
Wang, Qi; Navitskaya, Svetlana; Chakravarthy, Harshini et al. (2016) Dual Anti-Inflammatory and Anti-Angiogenic Action of miR-15a in Diabetic Retinopathy. EBioMedicine 11:138-150
Arjunan, Pachiappan; Gnanaprakasam, Jaya P; Ananth, Sudha et al. (2016) Increased Retinal Expression of the Pro-Angiogenic Receptor GPR91 via BMP6 in a Mouse Model of Juvenile Hemochromatosis. Invest Ophthalmol Vis Sci 57:1612-9
Markand, Shanu; Saul, Alan; Roon, Penny et al. (2015) Retinal Ganglion Cell Loss and Mild Vasculopathy in Methylene Tetrahydrofolate Reductase (Mthfr)-Deficient Mice: A Model of Mild Hyperhomocysteinemia. Invest Ophthalmol Vis Sci 56:2684-95
Lamoke, Folami; Shaw, Sean; Yuan, Jianghe et al. (2015) Increased Oxidative and Nitrative Stress Accelerates Aging of the Retinal Vasculature in the Diabetic Retina. PLoS One 10:e0139664
Bardhan, Kankana; Paschall, Amy V; Yang, Dafeng et al. (2015) IFN? Induces DNA Methylation-Silenced GPR109A Expression via pSTAT1/p300 and H3K18 Acetylation in Colon Cancer. Cancer Immunol Res 3:795-805
Elangovan, Selvakumar; Pathania, Rajneesh; Ramachandran, Sabarish et al. (2014) The niacin/butyrate receptor GPR109A suppresses mammary tumorigenesis by inhibiting cell survival. Cancer Res 74:1166-78
Promsote, Wanwisa; Veeranan-Karmegam, Rajalakshmi; Ananth, Sudha et al. (2014) L-2-oxothiazolidine-4-carboxylic acid attenuates oxidative stress and inflammation in retinal pigment epithelium. Mol Vis 20:73-88

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