Molecular basis of inflammation in retina, and novel strategies for limiting it

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DESCRIPTION (provided by applicant): 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.