Role of Photoreceptors in the Pathogenesis of Diabetic Retinopathy

光感受器在糖尿病视网膜病变发病机制中的作用

• 批准号: 10001512
• 负责人: Timothy S Kern
• 金额: $ 36.53万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001512
• 关键词: Adult; Adverse effects; Adverse reactions; Age; Blindness; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Brain; Cells; Characteristics; Clinical; Data; Defect; Developed Countries; Development; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Disease; Female; Functional disorder; Funding; Generations; Goals; Hyperglycemia; Inflammation; Inflammatory; Lead; Lesion; Leukocytes; Metabolic; Metabolic stress; Microvascular Dysfunction; Molecular; Molecular Abnormality; Mus; NADPH Oxidase; Oxidative Stress; Oxidative Stress Induction; Pathogenesis; Pathology; Photoreceptors; Play; Process; Proteins; RPE65 protein; Research; Retina; Retinal Degeneration; Retinal Diseases; Retinal Photoreceptors; Rhodopsin; Role; Secondary to; Stress; Structure; Structure of retinal pigment epithelium; Superoxides; Testing; Tissues; Vascular Diseases; Vision; Visual impairment; Work; cytokine; experience; extracellular; gray matter; inhibitor/antagonist; innovation; insight; knock-down; male; mouse model; mutant; new therapeutic target; novel; novel strategies; release factor; retina blood vessel structure; retinal damage; retinal rods; visual cycle

Diabetic retinopathy is clinically defined as a disease of the retinal microvasculature, and most research on its pathogenesis to date has focused on molecular and metabolic defects within the blood vessel cells themselves. In recent years, we have provided evidence that cells in the outer retina play a critical role the development of diabetic retinopathy. The current application will investigate the hypothesis that visual cycle activity plays a key role in initiation of the degenerative vascular lesions in early stages of diabetic retinopathy, and does this by increasing oxidative stress and inflammation within rod photoreceptors. Ultimately, the stressed photoreceptors release soluble factors (including cytokines) that damage the vasculature secondary to activating circulation leukocytes. Thus, the central hypothesis of our proposal is that hyperglycemia or other abnormalities that stress photoreceptors (such as rhodopsin mutants) lead to generation superoxide and other reactive products, and that these abnormalities initiate the structural and functional changes of the microvasculature which are clinically recognized as early diabetic retinopathy. Specific Aims will be: (1) to evaluate the roles of visual cycle activity in the retinal capillary damage caused by diabetes., (2) to investigate the roles of oxidative stress and/or inflammation within photoreceptors to initiate damage to the retinal vasculature, and (3) to identify soluble factors released by photoreceptors in diabetes, and mechanism by which those factors contribute to retinal capillary damage. The research proposed in Aim 1 will use mouse models in which RPE65 and LRAT are deficient, as well as a novel inhibitor of RPE65 to assess visual cycle activity. Aim 2 will be tested using mice having (i) photoreceptor-specific knockdown of activities of NADPH oxidase activity and NF-ĸB activation. Diabetes will be induced experimentally in male and female mice. This is a highly novel and testable hypothesis that will be conducted by an experienced research team. Confirmation of retinal photoreceptor cells as contributors to retinal capillary disease in DR (and other retinal vascular diseases) will offer several novel approaches to inhibit the development of these retinopathies.

糖尿病性视网膜病被临床定义为视网膜微脉管系统的疾病，大多数 迄今为止其发病机理的研究集中在分子和代谢缺陷上 血管细胞本身。近年来，我们提供了证据表明 外视网膜在糖尿病性视网膜病的发展中起着至关重要的作用。当前的应用程序 将研究视觉循环活动在开始中起关键作用的假设 在糖尿病性视网膜病的早期阶段，退化性血管病变，通过 增加棒感光体内的氧化应激和感染。最终，强调 感受器释放损坏脉管系统的固体因子（包括细胞因子） 继发于激活循环白细胞。那是我们提议的核心假设是 强调光感受器的高血糖或其他异常（例如Rhodopsin 突变体）导致产生的超氧化物和其他反应性产物，这些产品 异常引发了微脉管系统的结构和功能变化 临床上被认为是早期糖尿病性视网膜病。 具体目标是：（1）评估视觉循环活动在视网膜毛细管中的作用 糖尿病造成的损害。（2）研究氧化应激和/或注射的作用 在光感受器内启动对视网膜脉管系统的损害，（3）识别可溶性 光感受器在糖尿病中释放的因素以及这些因素的机制 导致视网膜毛细管损伤。 AIM 1中提出的研究将使用鼠标模型 哪个RPE65和LRAT不足，以及一种新颖的RPE65抑制剂来评估视觉 周期活动。 AIM 2将使用具有（i）特定于感光受体的小鼠进行测试 NADPH氧化物活性和NF-ĸB激活的活性。糖尿病将被诱发 在雄性和雌性小鼠中实验。这是一个高度新颖且可检验的假设 由经验丰富的研究团队进行。确认残留感光细胞为 DR（以及其他永久性血管疾病）的视网膜毛细血管疾病的贡献者将提供 几种抑制这些视网膜病的发展的新方法。