Role of Nrf2 in retinal vascularization and ROP

描述(申请人提供)：早产儿视网膜病变(ROP)在美国和其他发达国家的儿科人群中是导致失明的主要原因。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。视网膜无血管导致ROP的视力损害：缺血/缺氧的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的血管内皮生长因子。ROP视网膜无血管形成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中氧化应激和炎症的能力，从而促进生理性视网膜血管的形成，将对ROP的治疗大有裨益。事实上，促进视网膜血管重建在各种视网膜疾病中是非常可取的，特别是缺血性视网膜病变。转录因子Nrf2对氧化具有重要的细胞保护作用 在多种疾病过程中的应激和炎症。NRF2很容易受到药物调节，因此其保护作用可以增强。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，在氧诱导的视网膜病变中也有类似的证据。我们推测，Nrf2是促进缺血视网膜血管形成的重要机制，通过调节NADPH氧化酶调节视网膜的氧化应激和促炎变化。我们提出以下3个目标：1.研究Nrf2在视网膜新生血管和病理性视网膜新生血管中的作用；2.研究Nrf2通过调节NADPH氧化酶调节OIR的氧化应激和促炎过程的假说。具体目的3.确定Nrf2的药理活性是否对氧诱导的视网膜病变的病理生理和功能变化具有保护作用。我们期望这些目标将使我们能够确定Nrf2在氧诱导的视网膜病变中是一个重要的保护机制，从而为ROP提供新的治疗策略。

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.