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

视网膜炎症的分子基础以及限制炎症的新策略

• 批准号: 8787469
• 负责人: Pamela M Martin
• 金额: $ 36.75万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787469
• 关键词: Adipocytes; Adult; Advanced Development; Affect; Age related macular degeneration; Agonist; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Atherosclerosis; Biochemical; Biological Assay; Biological Models; Blindness; Blood Vessels; Cardiovascular Diseases; Cell Culture System; Cell model; Cell physiology; Cells; Characteristics; Chemosensitization; Cholesterol Homeostasis; Chronic; Clinical; Degenerative Disorder; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Disease Progression; Drug usage; Early Intervention; Endothelial Cells; Epithelial; Event; Functional disorder; G-Protein-Coupled Receptors; Goals; Health; Histocompatibility Testing; Homeostasis; Hyperlipidemia; Immune; Immunity; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Investigation; Knock-out; Knockout Mice; Laboratories; Lead; Ligands; Lipids; Lipoproteins; Maintenance; Microglia; Molecular; Monitor; Mus; Nicotinic Acids; Oxidative Stress; Pathogenesis; Pathologic; Pathway interactions; Prevention; Preventive Intervention; Primary Cell Cultures; Process; Property; Publishing; Receptor Activation; Regulation; Reporting; Research; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Retinal Pigments; Role; Structure of retinal pigment epithelium; Sum; System; Testing; Thrombosis; Tissues; Vision; Work; angiogenesis; base; blood lipid; cell type; clinically relevant; combat; diabetic; effective therapy; experience; improved; in vivo; innovation; interest; macrophage; monocyte; mouse model; novel; novel strategies; prevent; protective effect; receptor; receptor expression; repaired; response; therapeutic target; vascular inflammation

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.

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GPR109A来开发糖尿病性视网膜病（DR）的新疗法。炎症对于DR的发病机理至关重要。然而，目前，减少视网膜中糖尿病引起的炎症的临床策略有限。因此，迫切需要确定新的抗炎目标和策略。 GPR109A是降脂剂烟酸的受体。除了其抗酸性作用， 在功能上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。我们最近发表了有关RPE中GPR109a表达的第一份报告，我们实验室中的初步工作表明了该受体在小胶质细胞和内皮细胞中的表达也令人信服。 RPE，内皮细胞和小胶质细胞在视网膜中的免疫和炎症调节中都有已知作用，并且在DR的发病机理中受到严重影响。因此，我们预测GPR109A在这些细胞中也具有抗炎作用。 GPR109A具有抗炎作用的证据，影响了其他多种细胞过程，包括：维持能量稳态，氧化应激，脂质/胆固醇稳态和血管生成，在糖尿病性视网膜中也非常需要的作用，使GPR109A成为极具吸引力的治疗靶标。因此，我们的假设是，在视网膜中，GPR109A在多个点上破坏/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的发育和进展。为了检验这一假设，我们已开发并随时可用于实验室，许多创新的小鼠模型系统，包括GPR019A-KNOCKOUT，用于RPE的原代细胞培养系统，用于RPE的原代细胞培养系统，小胶质细胞和内皮细胞以及独特的测定系统，以监测不同的激动剂，药理学和内源性的GPR109A激活GPR109A。迄今为止，还没有对Retina的GPR109A进行调查。如果可以确定受体在与DR的发病机理/进展相关的过程中的作用（我们目前的目标），则受体将对预防和/或早期干预该疾病产生相当大的影响。拟议的研究很重要，因为它代表了一项连续研究的第一步，该研究预计会导致有效的药理学策略来调节GPR109A活性，从而在视网膜中发炎。