Role of Photoreceptors in the Pathogenesis of Diabetic Retinopathy

描述（由申请人提供）：糖尿病视网膜病变在临床上被定义为一种视网膜微血管疾病，迄今为止大多数关于其发病机制的研究都集中在血管细胞本身的分子和代谢缺陷上。近年来，一些论文认为外视网膜细胞可能在糖尿病视网膜病变的发展中起作用，但很少有与这些观点相关的后续研究。目前的应用将研究光感受器在糖尿病视网膜病变早期退行性血管病变的发生中起关键作用的假设，这一过程是由光感受器细胞的氧化应激启动的。氧化应激可以调节促炎蛋白的表达，我们之前的研究表明炎症在视网膜病变的早期阶段起重要作用。因此，我们建议的中心假设是，光感受器在糖尿病中产生超氧化物和其他反应性产物，这些异常（通过视网膜内部的局部炎症改变）引发微血管的结构和功能改变，这在临床上被认为是早期糖尿病视网膜病变。我们进一步预测，黑暗会加剧糖尿病视网膜血管的氧化和炎症作用，而光照可以抑制这些作用。提出的研究将使用光感受器退化或在视觉周期活动或光传导方面功能受损的小鼠模型，

DESCRIPTION (provided by applicant): 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 th 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.