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

Project: Research projectResearch Project

Description

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.
StatusActive
Effective start/end date1/1/1412/31/18

Funding

  • National Institutes of Health: $96,796.00
  • National Institutes of Health: $375,000.00
  • National Institutes of Health: $471,047.00
  • National Institutes of Health: $367,500.00

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Retina
Diabetic Retinopathy
Inflammation
Anti-Inflammatory Agents
Microglia
Endothelial Cells
Homeostasis
Lipids
Primary Cell Culture
Niacin
G-Protein-Coupled Receptors
Immunity
Oxidative Stress
Cholesterol
Maintenance
Research
Therapeutics

Keywords

  • Medicine(all)