Promotion of retinal vascular hyperpermeability and macular edema by ANGPTL4

概括。 缺血性视网膜病（IR）是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。最近推出的靶向疗法 高通透因子（HPF）、血管内皮生长因子（VEGF） 对两种最常见的黄斑水肿 (ME) 患者的治疗产生巨大影响 IR、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 VEGF”疗法显示，其中近一半的患者视力改善有限 尽管接受治疗的患者仍然存在，强调确定新的、安全的和有效的目标的紧迫性 用于治疗 IR 患者的 ME。在这方面，缺氧诱导的具有里程碑意义的发现 因子 (HIF)-1α，一种调节数百个基因表达的转录增强子 （包括 VEGF）使缺氧细胞和缺血组织适应低氧条件 张力，为 IR 的发病机制提供了基本的见解。 HIF-1的表达为 在 IR 动物模型以及 IR 患者中，视网膜内层 Müller 胶质细胞数量增加， 导致 HIF 调节基因的表达增加。尽管如此，还是有几个问题 仍然没有答案：1) VEGF 是唯一在 HIF 调节中发挥（重要）作用的基因吗？ IR 中内部血视网膜屏障 (iBRB) 完整性的破坏和 ME 的促进 患者（即 VEGF 是治疗 ME 的唯一良好的 HIF 调节靶标吗？） 2) 如果不是，哪个 其他 HIF 监管的 HPF 参与 IR 中 ME 的推广吗？ 3) 表达水平 这些其他 HPF 在对抗 VEGF 反应不足的 IR 患者眼中更高 疗法？ 4) 最后，针对多个因素是否是一种更有效的方法？ IR 中 ME 的治疗？这里提出的研究将解决我们的这些基本差距 知识。然而，并没有确认在其他缺血性中发现的已知 HPF 疾病也通过IR表达，我们的实验室已着手识别并全面检查 新型（尚未研究的）HPF 有助于这些患者的 ME。使用无偏见（不可知论） 方法，我们是第一个将血管生成素样 4 (ANGPTL4) 鉴定为有效的 HPF IR 中缺氧的视网膜内层中 HIF 上调。这一发现可以代表一个范例 我们对 ME 发病机制的理解发生了转变，意义重大，因为它揭示了一种新的机制 IR 患者 ME 治疗的治疗目标，包括那些有反应的患者 抗 VEGF 治疗不充分。该提案的目的是询问分子 ANGPTL4促进视网膜血管通透性过高的机制，以达到最终目标 设计新的治疗药物来治疗 ME。

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.