Promotion of retinal vascular hyperpermeability and macular edema by ANGPTL4

总结。 缺血性视网膜病变(IRS)是导致工作年龄严重视力障碍的主要原因 美国人，仍然是一个主要的公共卫生问题。最近推出的靶向治疗方法 高通透性因子(HPF)，血管内皮生长因子(VEGF)，已有 戏剧性影响黄斑水肿(ME)患者的治疗 IRS、糖尿病和视网膜静脉阻塞(RVO)。然而，评估疗效的临床试验 的“抗血管内皮生长因子”疗法显示，其中近一半患者的视力改善有限。 患者不顾治疗，强调了确定新的、安全和有效的靶点的紧迫性 用于治疗IR患者的ME。在这方面，低氧诱导的里程碑式的发现 缺氧诱导因子-1α，一种转录增强子，调节数百个基因的表达 (包括血管内皮生长因子)使缺氧细胞和缺血组织适应低氧条件 张力，为IRS的发病机制提供了基本的见解。HIF-1的表达为 在IR动物模型和IR患者中，视网膜内视网膜Müler胶质细胞增加， 导致HIF调控基因表达增加。尽管如此，有几个问题 仍然没有答案：1)血管内皮生长因子是唯一受缺氧诱导因子调控的基因，在 血-视网膜内屏障(IBRB)完整性的破坏和ME在IR中的促进作用 患者(即，血管内皮生长因子是治疗ME的唯一良好的HIF调节靶点吗？)2)如果不是， 其他受HIF调控的HPF在IRS中参与促进ME？3)的表达水平 在对抗血管内皮生长因子反应不足的IR患者中，这些其他HPF的水平较高 治疗？4)最后，针对多个因素是否是治疗 美国国税局对我的待遇？这里提出的研究将解决我们在 知识。然而，不是确认在其他缺血性疾病中发现的已知HPF 疾病也表现在国税局，我们的实验室已经着手识别和全面检查 新的(未被研究的)HPF对这些患者的ME有贡献。使用不偏不倚(不可知论者) 方法，我们已首次发现血管生成素样蛋白4(ANGPTL4)是一种有效的HPF 缺氧诱导因子上调IRS缺氧性内视网膜的表达。这一发现可能代表了一种范式 我们对ME发病机制的理解发生了重大转变，因为它揭示了一种新的 IR患者ME的治疗靶点，包括有反应的患者 抗血管内皮细胞生长因子治疗不足。这项提议的目的是询问分子 ANGPTL4促进视网膜血管高通透性的机制 设计新的治疗药物来治疗我。

SUMMARY. Ischemic retinopathies (IRs), the leading cause of severe vision impairment in working-age Americans, remain a major public health concern. The recent introduction of therapies targeting the hyper-permeability factor (HPF), vascular endothelial growth factor (VEGF), has had a dramatic impact on the treatment of macular edema (ME) in patients with the two most common IRs, diabetes and retinal vein occlusions (RVOs). However, clinical trials assessing the efficacy of “anti-VEGF” therapies have demonstrated limited improvement in vision in almost half of these patients despite treatment, underscoring the urgency to identify new, safe, and effective targets for the treatment of ME in IR patients. In this regard, the landmark discovery of hypoxia-inducible factor (HIF)-1α, a transcriptional enhancer that regulates the expression of hundreds of genes (including VEGF) that adapt hypoxic cells and ischemic tissues to conditions of low oxygen tension, has provided fundamental insight into the pathogenesis of IRs. Expression of HIF-1 is increased in retinal Müller glial cells in the inner retina in IR animal models as well as in IR patients, resulting in an increase in the expression of HIF-regulated genes. Nonetheless, several questions remain unanswered: 1) Is VEGF the only HIF-regulated gene that plays a (significant) role in the disruption of the integrity of the inner blood-retinal barrier (iBRB) and the promotion of ME in IR patients (i.e., is VEGF the only good HIF-regulated target for the treatment of ME?) 2) If not, which other HIF-regulated HPFs participate in the promotion of ME in IRs? 3) Are the expression levels of these other HPFs higher in the eyes of IR patients who respond inadequately to anti-VEGF therapies? 4) And finally, could targeting multiple factors be a more effective approach for the treatment of ME in IRs? The research proposed here will address these fundamental gaps in our knowledge. However, rather than confirming that known HPFs identified in other ischemic diseases are also expressed in IRs, our lab has set out to identify and comprehensively examine novel (understudied) HPFs that contribute to ME in these patients. Using an unbiased (agnostic) approach, we have been the first to identify Angiopoietin-like 4 (ANGPTL4) as a potent HPF upregulated by HIF in the hypoxic inner retina in IRs. This discovery could represent a paradigm shift in our understanding of the pathogenesis of ME and is significant because it exposes a novel therapeutic target for the treatment of ME in IR patients, including those who respond inadequately to anti-VEGF therapy. The objective of this proposal is to interrogate the molecular mechanisms by which ANGPTL4 promotes retinal vascular hyper-permeability with the final goal of designing novel therapeutic drugs to treat ME.