Role of Photoreceptors in the Pathogenesis of Diabetic Retinopathy

描述(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，到目前为止，对其发病机制的研究大多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，但很少有与这些想法相关的后续研究。目前的应用将探讨一种假说，即光感受器在糖尿病视网膜病变早期退行性血管病变的启动中起关键作用，并且这一过程是由光感受器细胞中的氧化应激启动的。众所周知，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发挥着重要作用。因此，我们的建议的中心假设是，在糖尿病中，光感受器产生超氧化物和其他反应产物，这些异常启动(通过视网膜内部局部炎症变化)微血管的结构和功能变化，这被临床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的氧化和炎症效应将在黑暗中加剧，而在光照下可被抑制。拟议的研究将使用小鼠模型，在该模型中，光感受器退化或在视觉周期活动或光传导方面功能受损， 或者是野生动物。糖尿病将在实验中诱发。具体目标将是：(1)区分光感受器、光转导和视觉周期活动在糖尿病引起的早期糖尿病视网膜病变血管病变中的作用；(2)评价光感受器在糖尿病视网膜氧化应激和促炎蛋白诱导(已被证明有助于早期糖尿病视网膜病变的血管病变)中的作用机制；以及(3)确定抑制光感受器中的氧化应激是否能够抑制糖尿病引起的视网膜血管结构和功能缺陷。目标3将使用(I)光感受器特异性抑制NADPH氧化酶(作为比较，(Ii)全身性抑制NADPH氧化酶)和(Iii)远红光治疗的小鼠进行测试。这是一个非常新颖和可验证的假设，将由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.