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

描述(由申请人提供)：该项目寻求通过靶向抗炎G蛋白偶联受体Gpr109a来开发治疗糖尿病视网膜病变(DR)的新疗法。炎症在DR的发病机制中起着至关重要的作用，然而，目前，减少糖尿病引起的视网膜炎症的临床策略有限。因此，迫切需要确定新的抗炎目标和战略。Gpr109a是降脂剂烟酸的受体。除了它的抗脂作用外， 众所周知，它在某些细胞类型/组织类型中具有强大的抗炎作用，这一现象在视网膜中尚未被研究过。最近，我们发表了第一份关于Gpr109a在RPE中表达的报告，我们实验室的初步工作证明，该受体也在小胶质细胞和内皮细胞中表达。RPE、内皮细胞和小胶质细胞都在调节视网膜的免疫和炎症中起着已知的作用，并且在DR的发病机制中起着至关重要的作用。因此，我们预测Gpr109a在这些细胞中也具有抗炎作用。有证据表明，TOP具有抗炎作用，Gpr109a影响其他多种细胞过程，包括：维持能量平衡、氧化应激、脂质/胆固醇平衡和血管生成，这些作用在糖尿病视网膜中也是非常可取的，使Gpr109a成为一个极具吸引力的治疗靶点。因此，我们的假设是，在视网膜，当激活时，Gpr109a在多个点扰乱/抑制促炎、促氧化和/或促血管生成途径，从而减少炎症和防止DR的发生和进展。为了检验这一假说，我们已经开发了许多创新的小鼠模型系统，包括Gpr019a基因敲除，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、药物和内源性Gpr109a激活的独特测试系统。到目前为止，还没有关于视网膜中Gpr109a的其他研究。如果受体在DR发病/进展过程中的作用得以确立(我们目前的目标)，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。这项拟议的研究意义重大，因为它代表了一系列研究的第一步，这一研究有望导致开发有效的药理学策略来调节Gpr109a的活性，从而调节视网膜的炎症。

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.