Regulation of diabetic retinopathy by Nrf2

 描述（由申请人提供）：糖尿病诱导的视网膜血管通透性变化（血-视网膜屏障功能障碍）是黄斑水肿的主要原因，黄斑水肿是糖尿病视网膜病变中视力丧失的最常见原因。抗VEGF疗法已成为保护甚至改善视觉功能的方法。然而，这种治疗只是部分有效，并不是所有人都有反应。有证据表明，多种其他因素导致血视网膜屏障功能障碍，包括肿瘤坏死因子和趋化因子（C-C基序）配体2（CCL 2）。因此，必须获得更多的见解，以便开发新的治疗策略。在寻找新的治疗方法的过程中，人们越来越认识到保护机制的重要性，这些机制可以抵消关键的致病过程，并认为增强这些保护机制可以延缓糖尿病视网膜病变的进展。该领域的另一个重要主题是对糖尿病视网膜病变的不同细胞类型（包括血管内皮细胞）的贡献的日益了解。在之前的资助期间，我们确定Nrf 2是糖尿病视网膜病变和其他视网膜疾病的重要保护机制，影响包括血视网膜屏障功能障碍和视网膜神经元功能障碍在内的多种过程。其作用的重要基础是Nrf 2抵消氧化应激并调节视网膜中的细胞因子环境。我们还发现，Nrf 2的药理学激活在视网膜血管疾病过程中具有保护作用，具有多个有益终点，包括神经保护。总之，这向我们表明，Nrf 2是DR治疗调节的有希望的候选者，特别是鉴于糖尿病可损害视网膜中Nrf 2活性的新证据。在这里，我们建议调查Nrf 2的保护作用的分子基础，以及确定糖尿病视网膜病变中Nrf 2作用的细胞背景。此外，我们将研究一种有前途的Nrf 2激活剂，用于治疗糖尿病视网膜病变中的血-视网膜屏障功能障碍。这些研究将为Nrf 2的有益作用机制提供新的见解，并为Nrf 2功能特别重要的特定细胞类型提供见解。验证Nrf的药理学靶向改善病理终点可能导致直接的临床转化，并暗示Nrf 2作为糖尿病黄斑水肿的新治疗靶点。

 DESCRIPTION (provided by applicant): Diabetes-induced changes in retinal vascular permeability (blood-retinal barrier dysfunction) are a major contributor to macular edema, the most common cause of visual loss in diabetic retinopathy. Anti-VEGF therapies have emerged as an approach to preserve or even improve visual function. However, this treatment is only partially effective and not all individuals respond. Evidence suggests that multiple other factors contribute to blood-retinal barrier dysfunction, including tumor necrosis factor and the chemokine (C-C motif) ligand 2 (CCL2). It is therefore essential to gain additional insights to allow the development of new therapeutic strategies. In the search for new treatments, there is increasing appreciation for the importance of protective mechanisms which could counteract key pathogenic processes, with the idea that enhancing these protective mechanisms could delay the progression of diabetic retinopathy. An additional important theme in the field is the growing understanding of the contribution of diverse cell types to diabetic retinopathy, including and in addition to vascular endothelial cells. During the previous funding period we identified Nrf2 as an important protective mechanism in diabetic retinopathy and other retinal conditions, impacting on diverse processes including blood-retinal barrier dysfunction and retinal neuronal dysfunction. An important basis for its action is that Nrf2 counteracts oxidative stress and regulates the cytokine environment in the retina. We also found that pharmacologic activation of Nrf2 is protective in retinal vascular disease processes, with multiple beneficial endpoints including neuroprotection. Taken together, this suggests to us that Nrf2 is a promising candidate for therapeutic modulation in DR, especially in light of emerging evidence that diabetes can impair Nrf2 activity in the retina. Here we propose to investigate the molecular basis for Nrf2's protective effect as well as to determine the cellular context for Nrf2 action in diabetic retinopathy. In addition, we will investigate a promising Nrf2 activator for treatment of blood-retinal barrier dysfunction in diabetic retinopathy. These studies will provide new insights into the mechanisms for Nrf2's beneficial effects as well as provide insights into the specific cell types in which Nrf2 function is particularly critical. Validation of pharmacologic targeting of Nrf for amelioration of pathologic endpoints could lead to direct clinical translation and implicate Nrf2 as a new therapeutic target for diabetic macular edema.