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

描述（由申请人提供）：该项目旨在通过靶向抗炎G蛋白偶联受体GPR 109 A开发糖尿病视网膜病变（DR）的新疗法。炎症在DR的发病机制中至关重要。然而，目前，减少糖尿病诱导的视网膜炎症的临床策略有限。因此，迫切需要鉴定新的抗炎靶标和策略。GPR 109 A是降脂药烟酸的受体。除了它的抗脂肪分解作用， 其在功能上被注意到在某些细胞类型/组织类型中引起有效的抗炎作用，这是一种尚未在视网膜中研究的现象。我们最近发表了关于GPR 109 A在RPE中表达的第一份报告，我们实验室的初步工作令人信服地证明了该受体在小胶质细胞和内皮细胞中的表达。RPE、内皮细胞和小胶质细胞各自在视网膜中的免疫和炎症调节中具有已知的作用，并且在DR的发病机制中受到严重影响。因此，我们预测GPR 109 A也在这些细胞中具有抗炎作用。证据表明，除了抗炎作用之外，GPR 109 A还影响多种其他细胞过程，包括：维持能量稳态、氧化应激、脂质/胆固醇稳态和血管生成，这些作用在糖尿病视网膜中也是高度期望的，使得GPR 109 A成为高度有吸引力的治疗靶标。因此，我们的假设是，在视网膜中，在激活时，GPR 109 A在多个点破坏/抑制促炎、促氧化和/或促血管生成途径，从而减少炎症并防止DR的发展和进展。为了测试该假设，我们已经开发了许多创新的小鼠模型系统，包括Gpr 019 a敲除、用于RPE、小胶质细胞和内皮细胞的原代细胞培养系统，以及用于监测不同激动剂（药理学和内源性）对GPR 109 A的激活的独特测定系统。到目前为止，还没有其他的研究GPR 109 A在视网膜。如果受体在与DR的发病机制/进展相关的过程中的作用可以确定（我们目前的目标），该受体将作为预防和/或早期干预该疾病的新的有效靶点产生相当大的影响。这项研究的意义在于它代表了一系列研究的第一步，这些研究有望导致开发有效的药理学策略来调节GPR 109 A活性，从而调节视网膜炎症。

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.