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: 8578728
• 负责人: Timothy S Kern
• 金额: $ 39.63万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578728
• 关键词: Adult; Adverse effects; Age; Animals; Blindness; Blood Vessels; Blood capillaries; Brain; Cells; Darkness; Defect; Developed Countries; Development; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Disease; Exposure to; Frequencies; Histopathology; Hyperglycemia; Inflammation; Inflammatory; Lesion; Light; Metabolic; Mitochondria; Molecular; Mus; NADPH Oxidase; Neurophysiology - biologic function; Oxidative Stress; Oxidative Stress Induction; Paper; Pathogenesis; Pathology; Photoreceptors; Phototherapy; Phototransduction; Play; Process; Proteins; Reporting; Research; Research Personnel; Retina; Retinal; Retinal Degeneration; Retinal Diseases; Role; Staging; Structure; Superoxides; Testing; Therapeutic; Tissues; Work; capillary; dehydroretinal; diabetic; diabetic patient; experience; follow-up; improved; inhibitor/antagonist; knock-down; light effects; mouse model; novel; public health relevance; response; retina blood vessel structure; 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, a few papers have suggested that cells in the outer retina might play a role the development of diabetic retinopathy, but there has been little follow-up pertaining to these ideas. The current application will investigate the hypothesis that photoreceptors play a key role in initiation of the degenerative vascular lesions in early stages of diabetic retinopathy, and that this process is initiated by oxidative stress in the photoreceptor cells. Oxidative stress is known to regulate expression of pro-inflammatory proteins, and previous studies by us have implicated an important role of inflammation in the early stages of the retinopathy. Thus, the central hypothesis of our proposal is that the photoreceptors generate superoxide and other reactive products in diabetes, and that these abnormalities initiate (via local inflammatory changes in the inner retina) the structural and functional changes of the microvasculature which are clinically recognized as early diabetic retinopathy. We further predict that oxidative and inflammatory effects on the retinal vasculature in diabetes will be exacerbated by darkness, and can be inhibited with light. The research proposed will use mouse models in which photoreceptors degenerate or are functionally impaired with respect to visual cycle activity or phototransduction, or wildtype animals. Diabetes will be induced experimentally. Specific Aims will be: (1) to differentiate the roles of photoreceptors, phototransduction and visual cycle activity in the development of the diabetes-induced vascular lesions of early diabetic retinopathy, (2) to evaluate the mechanisms by which photoreceptors contribute to the retinal oxidative stress and induction of pro-inflammatory proteins in diabetes (which have been shown to contribute to the vascular lesions of early diabetic retinopathy), and (3) to determine if inhibition of oxidative stress in photoreceptors results in inhibition of diabetes-induced defects in retinal vascular structure and function. Aim 3 will be tested using mice having (i) photoreceptor-specific knockdown of NADPH oxidase (and for comparison, (ii) systemic inhibition of NADPH oxidase), and (iii) far-red light therapy. This is a highly novel and testable hypothesis that will be conducted by an experienced research team.

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，一些论文表明 视网膜外部可能在糖尿病性视网膜病变的发展中发挥作用，但很少有 与这些想法有关的后续行动。当前的申请将调查以下假设 感光体在开始的早期阶段开始启动退化性血管病变中 糖尿病性视网膜病，并且该过程是通过感光器中的氧化应激引发的 细胞。已知氧化应激会调节促炎蛋白的表达，并调节 我们先前的研究暗示了在早期炎症的重要作用 视网膜病。因此，我们建议的核心假设是感光体产生 糖尿病中的超氧化物和其他反应性产物，这些异常开始（通过 内部视网膜的局部炎症变化） 在临床上被认为是糖尿病性视网膜病早期的微脉管系统。我们进一步预测 对糖尿病视网膜脉管系统的氧化和炎症作用将加剧 通过黑暗，可以用光抑制。提出的研究将使用鼠标模型 哪种光感受器退化或相对于视觉周期的功能受损 活性或光转导的动物。糖尿病将是通过实验诱导的。 具体目的是：（1）区分光感受器的作用，光转导和 糖尿病诱导的早期糖尿病的血管病变发展中的视觉周期活性 视网膜病变（2）评估感光体有助于视网膜的机制 糖尿病中促炎蛋白的氧化应激和诱导（已显示 为早期糖尿病性视网膜病的血管病变做出贡献），以及（3）是否确定是否是否 光感受器中氧化应激的抑制会导致抑制糖尿病诱导的缺陷 在视网膜血管结构和功能中。 AIM 3将使用具有（i）的小鼠进行测试 NADPH氧化酶的光感受器特异性敲低（并且为了进行比较，（II）系统性 抑制NADPH氧化酶）和（iii）远红色光疗法。这是一个非常新颖且可测试的 经验丰富的研究团队将进行的假设。