Promotion of retinal vascular hyperpermeability and macular edema by ANGPTL4

ANGPTL4 促进视网膜血管通透性过高和黄斑水肿

基本信息

批准号：
9769763
负责人：
SILVIA V MONTANER
金额：
$ 51.11万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769763
关键词：
ANGPTL4 gene Address Age American Animal Model Binding Blindness Blood Vessels Blood-Retinal Barrier Cells Clinical Trials Complement Data Development Diabetes Mellitus Disease Endothelial Cells Enhancers Exposure to Eye Genes Genetic Transcription Goals Hypoxia Hypoxia Inducible Factor In Vitro Investigation Knowledge Lead Link Mediating Molecular Molecular Target Muller&apos s cell Mus NRP1 gene Neuroglia Neuropilin-1 Neuropilin-2 Oxygen Pathogenesis Patients Permeability Pharmaceutical Preparations Play Public Health Receptor Cell Reporting Research Retina Retinal Retinal Diseases Retinal Neovascularization Retinal Vein Occlusion Role Signal Pathway Signal Transduction Tissues Treatment Efficacy Vascular Endothelial Growth Factors Vascular Permeabilities Vision Visual impairment base cytokine design hypoxia inducible factor 1 improved insight intravitreal injection macular edema mouse model new therapeutic target novel novel therapeutics receptor response retinal ischemia targeted treatment therapeutic target

项目摘要

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.

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最近推出的靶向疗法仍然是一个主要的公共卫生问题。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，临床试验正在评估其疗效。的“抗 VEGF”疗法显示，其中近一半的患者视力改善有限患者尽管接受治疗，强调了确定新的、安全的和有效的目标的紧迫性在这方面，缺氧诱导的 ME 治疗具有里程碑意义。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，为了解 HIF-1 的表达的发病机制提供了基本的见解。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，然而，这导致了 HIF 调节基因表达的增加，但有几个问题。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 调节的 HPF 参与 IR 中 ME 的促进 3) 表达水平是否相同？这些其他 HPF 在对抗 VEGF 反应不足的 IR 患者眼中更高 4）最后，针对多种因素是否是一种更有效的方法？这里提出的研究将解决我们在 IR 中的 ME 治疗？然而，这并没有证实在其他缺血性疾病中发现的已知 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使用无偏见（不可知论）的新的（未充分研究的）HPF 有助于这些患者的 ME。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 HIF 上调这一发现可能代表了一个范例。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 疗法的不足该提案的目的是询问分子水平。 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。