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，我们提供的证据表明， 外层视网膜在糖尿病视网膜病变的发展中起着关键作用。当前应用程序 将调查的假设，即视觉周期活动起着关键作用，在启动的 糖尿病视网膜病变早期的退行性血管病变， 增加视杆细胞内的氧化应激和炎症。最终，压力 光感受器释放损害脉管系统的可溶性因子（包括细胞因子 继发于激活循环白细胞。因此，我们建议的中心假设是 高血糖症或其他压迫光感受器的异常（如视紫红质 突变体）导致产生超氧化物和其他反应产物，并且这些 异常引发微脉管系统的结构和功能变化， 临床上被认为是早期糖尿病视网膜病变。 具体目的是：（1）评价视觉周期活动在视网膜毛细血管中的作用 糖尿病造成的损害，(2)研究氧化应激和/或炎症的作用 在光感受器内引发对视网膜脉管系统的损伤，以及（3）识别可溶性 糖尿病中光感受器释放的因子，以及这些因子 导致视网膜毛细血管损伤。目标1中提出的研究将使用小鼠模型， RPE 65和LRAT缺乏的，以及一种新的RPE 65抑制剂， 循环活动。Aim 2将使用具有（i）光受体特异性敲低的小鼠进行测试， NADPH氧化酶活性和NF-κ B活化。糖尿病会诱发 在雄性和雌性小鼠中进行实验。这是一个非常新颖和可检验的假设， 由经验丰富的研究团队进行。视网膜光感受器细胞的确认 DR中视网膜毛细血管疾病（和其他视网膜血管疾病）的贡献者将提供 几种新的方法来抑制这些视网膜病变的发展。

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, we have provided evidence that cells in the outer retina play a critical role the development of diabetic retinopathy. The current application will investigate the hypothesis that visual cycle activity plays a key role in initiation of the degenerative vascular lesions in early stages of diabetic retinopathy, and does this by increasing oxidative stress and inflammation within rod photoreceptors. Ultimately, the stressed photoreceptors release soluble factors (including cytokines) that damage the vasculature secondary to activating circulation leukocytes. Thus, the central hypothesis of our proposal is that hyperglycemia or other abnormalities that stress photoreceptors (such as rhodopsin mutants) lead to generation superoxide and other reactive products, and that these abnormalities initiate the structural and functional changes of the microvasculature which are clinically recognized as early diabetic retinopathy. Specific Aims will be: (1) to evaluate the roles of visual cycle activity in the retinal capillary damage caused by diabetes., (2) to investigate the roles of oxidative stress and/or inflammation within photoreceptors to initiate damage to the retinal vasculature, and (3) to identify soluble factors released by photoreceptors in diabetes, and mechanism by which those factors contribute to retinal capillary damage. The research proposed in Aim 1 will use mouse models in which RPE65 and LRAT are deficient, as well as a novel inhibitor of RPE65 to assess visual cycle activity. Aim 2 will be tested using mice having (i) photoreceptor-specific knockdown of activities of NADPH oxidase activity and NF-ĸB activation. Diabetes will be induced experimentally in male and female mice. This is a highly novel and testable hypothesis that will be conducted by an experienced research team. Confirmation of retinal photoreceptor cells as contributors to retinal capillary disease in DR (and other retinal vascular diseases) will offer several novel approaches to inhibit the development of these retinopathies.