Regulation of diabetic retinopathy by Nrf2

描述（由申请人提供）：糖尿病视网膜病变（DR）是工业化国家工作年龄成人失明的主要原因，由于全球糖尿病发病率的上升，其对公共卫生的影响将变得更大。糖尿病视网膜病变的视力损害由两个原因引起：视网膜血管通透性增加（导致糖尿病黄斑水肿）和毛细血管脱落（导致视网膜缺血/缺氧和随后视网膜新生血管形成）。糖尿病在视网膜中产生氧化应激和促炎性变化，这对于糖尿病视网膜病变的发病机制至关重要。因此，这些过程的调节对于DR的进展是重要的。转录因子Nrf 2在多种疾病过程中对氧化应激和炎症具有重要的细胞保护作用。nrf 2非常适合药理学调节，因此其保护作用可以增强。我们的实验室一直在研究Nrf 2在视网膜中的作用。我们已经发现Nrf 2系统在视网膜对缺血再灌注损伤的反应中起着重要的保护作用。此外，我们有初步证据表明Nrf 2在糖尿病视网膜病变中起着重要作用。我们假设Nrf 2是调节糖尿病视网膜氧化应激和促炎变化的重要保护机制。我们进一步假设Nrf 2调节糖尿病视网膜病变中的血管通透性和毛细血管脱落，并提出以下3个目标：具体目标1。在糖尿病小鼠模型中确定Nrf 2在氧化应激和促炎过程调节中的作用。具体目标2。在糖尿病小鼠模型中确定Nrf 2对血管通透性和毛细血管脱落的作用。具体目标3。确定Nrf 2的药理学激活是否可预防糖尿病视网膜病变的病理生理和功能变化。我们预计这些目标将使我们能够将Nrf 2作为糖尿病视网膜病变的重要保护机制，并为这种威胁视力的疾病提供新的治疗策略。

DESCRIPTION (provided by applicant): 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.