Regulation of diabetic retinopathy by Nrf2

糖尿病视网膜病变(DR)是工业化国家劳动年龄成年人失明的主要原因， 而由于世界糖尿病发病率的上升，其对公众健康的影响将变得更大-- 很宽。糖尿病视网膜病变的视力损害由两个原因引起：视网膜血管增加 通透性(导致糖尿病黄斑水肿)和毛细血管脱落(导致视网膜 缺血/缺氧和随后的视网膜新生血管的发展)。糖尿病引发氧化 视网膜中的应激和促炎性变化，这对糖尿病的发病机制至关重要 视网膜病变。因此，对这些过程的调节对DR的进展非常重要。 转录因子Nrf2对小鼠的氧化应激和炎症具有重要的细胞保护作用 多种疾病过程。NRF2很容易受到药物调节，所以它的保护作用可以 被增强了。我们的实验室一直在研究Nrf2在视网膜中的作用。我们发现NRF2系统 在视网膜对缺血再灌注损伤的反应中起着至关重要的保护作用。此外，我们还拥有 初步证据表明，Nrf2在糖尿病视网膜病变中起重要作用。我们假设NRF2是一个 大鼠视网膜氧化应激和促炎变化的重要保护机制 糖尿病。我们进一步假设Nrf2调节糖尿病患者的血管通透性和毛细血管脱落。 视网膜病变，并提出了以下3个目标：具体目标1.确定Nrf2在调节 糖尿病小鼠模型中的氧化应激和促炎过程。具体目标2.确定 Nrf2对糖尿病小鼠模型血管通透性和毛细血管脱落的作用。具体目标3. 确定Nrf2的药理激活是否对心脏病理生理和功能改变具有保护作用 糖尿病视网膜病变。我们预计，这些目标将使我们能够将NRF2作为一种重要的保护措施 糖尿病视网膜病变的发病机制，并为这种威胁视力的疾病提供了新的治疗策略。

Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults in industrialized countries, and its effects on public health will become even greater because of the rising incidence of diabetes world- wide. Visual impairment in diabetic retinopathy results from two causes: increased retinal vascular permeability (which leads to diabetic macular edema) and capillary drop-out (which leads to retinal ischemia/hypoxia and the subsequent development of retinal neovascularization). Diabetes creates oxidative stress and pro-inflammatory changes in the retina, which are critical for the pathogenesis of diabetic retinopathy. As a result, the regulation of these processes is important for the progression of DR. The transcription factor Nrf2 has an important cytoprotective role against oxidative stress and inflammation in multiple disease processes. Nrf2 is quite amenable to pharmacologic modulation, so its protective effects can be augmented. Our lab has been studying the role of Nrf2 in the retina. We have found that the Nrf2 system plays a vital protective role in the retinal response to ischemia-reperfusion injury. Furthermore, we have preliminary evidence that Nrf2 plays an important role in diabetic retinopathy. We hypothesize that Nrf2 is an important protective mechanism regulating oxidative stress and pro-inflammatory changes in the retina in diabetes. We further hypothesize that Nrf2 regulates vascular permeability and capillary dropout in diabetic retinopathy and propose the following 3 aims: Specific Aim 1. Determine the role of Nrf2 in the regulation of oxidative stress and pro-inflammatory processes in a diabetic mouse model. Specific Aim 2. Determine the role of Nrf2 on vascular permeability and capillary drop-out in a diabetic mouse model. Specific Aim 3. Determine if pharmacologic activation of Nrf2 protects against pathophysiologic and functional changes in diabetic retinopathy. We anticipate that these aims will allow us to implicate Nrf2 as an important protective mechanism in diabetic retinopathy and provide a new therapeutic strategy for this sight-threatening condition.