Role of Nrf2 in retinal vascularization and ROP

描述（由申请人提供）：早产儿视网膜病变（ROP）是美国和其他发达国家儿童人群失明的主要原因。早期ROP的一个关键方面是视网膜无血管的发展，这导致ROP和视网膜NV的晚期。ROP中的视觉损害由视网膜无血管性引起：缺血/缺氧视网膜产生促血管生成生长因子，包括刺激视网膜新生血管形成的VEGF。ROP中视网膜无血管性的重要病理生理过程，包括氧化应激和促炎过程。因此，调节ROP中的氧化应激和炎症的能力，从而促进生理性视网膜血管化，将在ROP的治疗中具有很大的益处。事实上，在各种视网膜疾病，特别是缺血性视网膜病变中，促进血管再生是非常需要的。转录因子Nrf 2具有重要的细胞保护作用， 应激和炎症在多种疾病过程中的作用。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在缺血-再灌注损伤的视网膜反应中起着重要的保护作用，并且在氧诱导的视网膜病变的背景下也有类似的证据。我们假设Nrf 2是促进缺血性视网膜的视网膜血管化、通过调节NADPH氧化酶调节视网膜中的氧化应激和促炎性变化的重要机制。我们提出以下三个目标：具体目标1。研究Nrf 2在视网膜血管重建和病理性视网膜新生血管中的作用。研究Nrf 2通过调节NADPH氧化酶调节OIR中的氧化应激和促炎过程的假设。具体目标3。确定Nrf 2的药理学激活是否可防止氧诱导视网膜病变的病理生理和功能变化。我们希望这些目标将使我们能够确定Nrf 2作为氧诱导视网膜病变的重要保护机制，从而为ROP提供新的治疗策略。 公共卫生相关性：早产儿视网膜病变（ROP）是美国和其他发达国家儿童人群失明的主要原因。这项研究将使我们能够使用这种情况的小鼠模型来研究保护分子Nrf 2的有益作用。这可能使我们能够开发一种新的治疗早产儿视网膜病变的方法，旨在增强Nrf 2的有益作用。

DESCRIPTION (provided by applicant): Retinopathy of prematurity (ROP) is the leading cause of blindness in the U.S. and other developed countries in the pediatric population. A pivotal aspect of early ROP is the development of retinal avascularity, which leads to advanced stages of ROP and retinal NV. Visual impairment in ROP results from retina avascularity: the ischemic/hypoxic retina produces pro-angiogenic growth factors including VEGF which stimulates retinal neovascularization. Important pathophysiologic processes underlie retinal avascularity in ROP, including oxidative stress and pro-inflammatory processes. The ability to modulate oxidative stress and inflammation in ROP, thereby facilitating physiologic retinal vascularization, would therefore be of great benefit in the treatment of ROP. Indeed, promotion of revascularization is highly desirable in a variety of retinal diseases, particularly the ischemi retinopathies. 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 Nrf2 plays a vital protective role in the retinal response t ischemia-reperfusion injury, and have similar evidence in the context of oxygen-induced retinopathy. We hypothesize that Nrf2 is an important mechanism promoting retinal vascularization of ischemic retina, regulating oxidative stress and pro- inflammatory changes in the retina via modulation of NADPH oxidase. We propose the following 3 aims: Specific Aim 1. Investigate the role of Nrf2 in retinal revascularization and pathologic retinal neovascularization Specific Aim 2. Investigate the hypothesis that Nrf2 regulates oxidative stress and pro- inflammatory processes in OIR via modulation of NADPH oxidase. Specific Aim 3. Determine if pharmacologic activation of Nrf2 protects against pathophysiologic and functional changes in oxygen-induced retinopathy. We expect that these aims will allow us to identify Nrf2 as an important protective mechanism in oxygen-induced retinopathy, thereby providing a new therapeutic strategy for ROP. PUBLIC HEALTH RELEVANCE: Retinopathy of prematurity (ROP) is the leading cause of blindness in the U.S. and other developed countries in the pediatric population. This research will allow us to investigate the beneficial role of the protective molecule Nrf2 using a mouse model for this condition. This could allow us to develop a new therapy for retinopathy of prematurity, aimed at enhancing the beneficial effects of Nrf2.