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视网膜微血管疾病，迄今为止对其发病机制的大多数研究都集中在血管细胞本身的分子和代谢缺陷上。近年来，一些论文提出外层视网膜中的细胞可能在糖尿病视网膜病变的发展中发挥作用，但很少有关于这些想法的后续研究。本申请将研究以下假设：光感受器在糖尿病视网膜病变的早期阶段的退行性血管病变的起始中起关键作用，并且该过程由光感受器细胞中的氧化应激起始。已知氧化应激调节促炎蛋白的表达，并且我们先前的研究已经暗示炎症在视网膜病变的早期阶段中的重要作用。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产物，并且这些异常启动（通过内部视网膜中的局部炎症变化）微血管的结构和功能变化，其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，糖尿病患者视网膜血管系统的氧化和炎症作用将因黑暗而加剧，并可通过光照抑制。这项研究将使用小鼠模型，其中光感受器退化或在视觉周期活动或光转导方面功能受损， 或野生型动物。糖尿病将通过实验诱导。具体目标是：（1）区分光感受器、光传导和视觉周期活动在糖尿病诱导的早期糖尿病视网膜病变的发展中的作用;（2）评估光感受器在糖尿病视网膜氧化应激和促炎蛋白诱导中的作用机制（已显示其有助于早期糖尿病视网膜病变的血管病变），和（3）确定光感受器中氧化应激的抑制是否导致糖尿病的抑制-导致视网膜血管结构和功能的缺陷。目标3将使用具有（i）NADPH氧化酶的光受体特异性敲低（并且为了比较，（ii）NADPH氧化酶的全身性抑制）和（iii）远红光疗法的小鼠进行测试。这是一个非常新颖和可验证的假设，将由一个经验丰富的研究团队进行。

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.