Role of Photoreceptors in the Pathogenesis of Diabetic Retinopathy

糖尿病视网膜病变在临床上被定义为视网膜微血管疾病，大多数 到目前为止，对其发病机制的研究主要集中在体内的分子和代谢缺陷上。 血管细胞本身。近年来，有几篇论文提出，细胞在 外视网膜可能在糖尿病视网膜病变的发展中起作用，但一直很少。 与这些想法有关的后续行动。当前的应用程序将调查以下假设 光感受器在早期退行性血管病变的启动中起关键作用 糖尿病视网膜病变，这一过程是由光感受器中的氧化应激启动的 细胞。众所周知，氧化应激可以调节促炎蛋白的表达，并且 我们之前的研究表明，炎症在糖尿病早期阶段起着重要作用。 视网膜病变。因此，我们建议的中心假设是光感受器产生 糖尿病中的超氧化物和其他反应产物，并且这些异常开始(通过 视网膜内的局部炎症改变)视网膜结构和功能的改变 临床上被认为是早期糖尿病视网膜病变的微血管。我们进一步预测 糖尿病患者视网膜血管的氧化和炎症反应将会加剧 在黑暗中，可以用光来抑制。拟议中的研究将使用老鼠模型 哪些光感受器在视觉周期方面退化或功能受损 活动或光传导，或野生动物。糖尿病将在实验中诱发。 具体目标将是：(1)区分光感受器、光转导和 视觉循环活动在早期糖尿病血管病变发生发展中的作用 视网膜病变，(2)评估光感受器对视网膜的作用机制 糖尿病患者的氧化应激和促炎蛋白的诱导(已证实 以促进早期糖尿病视网膜病变的血管病变)，以及(3)确定 抑制光感受器的氧化应激导致糖尿病引起的缺陷的抑制 视网膜血管的结构和功能。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除(为比较，(Ii)系统 抑制NADPH氧化酶)，以及(Iii)远红光疗法。这是一种非常新颖和可测试的 假设将由经验丰富的研究团队进行。

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.