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系统的疾病，并且大多数糖尿病视网膜病变都是视网膜病变。 迄今为止，关于其发病机理的研究集中在细胞内的分子和代谢缺陷， 血管细胞本身。近年来，一些论文提出， 外视网膜可能在糖尿病视网膜病变的发展中起作用，但很少有 这些想法的后续行动。本申请将研究以下假设， 光感受器在退行性血管病变的早期阶段起关键作用， 糖尿病视网膜病变，这一过程是由光感受器中的氧化应激引发的 细胞已知氧化应激调节促炎蛋白的表达， 我们以前的研究已经暗示了炎症在早期阶段的重要作用。 视网膜病变因此，我们建议的中心假设是，光感受器产生 超氧化物和其他反应产物，这些异常启动（通过 视网膜内层的局部炎性变化）的结构和功能变化， 糖尿病视网膜病变的早期症状是微血管病变，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加剧 黑暗中，可以用光来抑制。这项研究将使用小鼠模型， 哪些光感受器退化或功能受损 活性或光转导，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，光转导和 视觉周期活动在早期糖尿病血管病变中的作用 视网膜病变，（2）评估光感受器促进视网膜病变的机制 糖尿病中的氧化应激和促炎蛋白的诱导（已经显示 有助于早期糖尿病视网膜病变的血管病变），和（3）确定是否 抑制光感受器中的氧化应激导致抑制糖尿病诱导的缺陷 视网膜血管结构和功能。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）全身性 NADPH氧化酶的抑制），和（iii）远红光疗法。这是一个高度新颖和可测试的 这将由一个经验丰富的研究团队进行假设。

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.