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

基本信息

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
项目类别：
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

项目摘要

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.

糖尿病视网膜病变在临床上被定义为视网膜微血管系统疾病，大多数迄今为止，对其发病机制的研究主要集中在细胞内的分子和代谢缺陷上。近年来，我们提供的证据表明，血管细胞本身。外视网膜在糖尿病视网膜病变的发展中起关键作用。将研究视觉周期活动在启动视觉循环中起关键作用的假设糖尿病视网膜病变早期阶段的退行性血管病变，并通过以下方法做到这一点增加视杆细胞内的氧化应激和炎症，最终导致应激。光感受器释放可溶性因子（包括细胞因子），损害脉管系统继发于激活循环白细胞因此，我们建议的中心假设是高血糖或其他对光感受器造成压力的异常（例如视紫红质）突变体）导致超氧化物和其他反应产物的产生，并且这些异常会引发微血管的结构和功能变化临床上被认为是早期糖尿病视网膜病变。具体目标是：（1）评估视觉周期活动在视网膜毛细血管中的作用糖尿病引起的损害。，(2) 研究氧化应激和/或炎症的作用在光感受器内启动对视网膜脉管系统的损害，以及（3）识别可溶性糖尿病中光感受器释放的因子，以及这些因子的机制导致视网膜毛细血管损伤。目标 1 中提出的研究将使用小鼠模型。 RPE65 和 LRAT 缺陷，以及用于评估视觉的新型 RPE65 抑制剂目标 2 将使用具有 (i) 光感受器特异性敲低的小鼠进行测试。 NADPH氧化酶活性和NF-ĸB激活将被诱导。这是一个非常新颖且可测试的假设，将在雄性和雌性小鼠中进行实验。由经验丰富的研究团队进行视网膜感光细胞的确认。 DR 中视网膜毛细血管疾病（和其他视网膜血管疾病）的贡献者将提供抑制这些视网膜病变发展的几种新方法。