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：
10006543
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006543
关键词：
ANGPTL4 gene Address Age American Animal Model Binding Blindness Blood Vessels Blood-Retinal Barrier Cell Hypoxia 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 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 damage 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。缺血性视网膜病变（IRS），这是劳动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。最近引入靶向疗法高渗透率因子（HPF），血管内皮生长因子（VEGF）具有两种最常见的患者对黄斑水肿（ME）的治疗的巨大影响 IRS，糖尿病和视网膜静脉阻塞（RVO）。但是，评估效率的临床试验 “抗VEGF”疗法的视觉改善有限，其中几乎一半患者目的地治疗，强调识别新，安全和有效目标的紧迫性为了在IR患者中治疗我。在这方面，具有里程碑意义的发现缺氧诱导因子（HIF）-1α，一种调节数百个基因表达的转录增强子（包括VEGF）将低氧细胞和缺血组织适应低氧的条件张力为IRS的发病机理提供了基本的见解。 HIF-1的表达为 IR动物模型以及IR患者的视网膜视网膜胶质神经胶质细胞的增加导致HIF调节基因表达的增加。尽管如此，有几个问题保持未解决：1）是VEGF是唯一在HIF调节的基因中起着（）在内部血视网膜屏障（IBRB）的完整性的破坏和IR中的促进患者（即VEGF是唯一的HIF调节靶标？）2）如果不是，哪个，哪个其他由HIF调节的HPF参与IRS晋升的HPF？ 3）是表达水平在对抗VEGF反应不足的IR患者眼中，这些其他HPF较高治疗？ 4）最后，可以针对多种因素是一种更有效的方法在IRS中对我的待遇？这里提出的研究将解决我们的这些基本差距知道。但是，而不是确认其他缺血性鉴定的已知HPF IRS也表达了疾病，我们的实验室已着手识别和全面检查这些患者对我有贡献的新颖（已理解）HPF。使用公正（不可知）方法，我们是第一个将类似Angiopietin的4（Angptl4）识别为潜在HPF的人在IRS中的低氧内部视网膜中，HIF上调。这个发现可能代表范式我们对我发病机理的理解的转变，并且很重要，因为它暴露了一个新颖的在IR患者中，包括反应的人，包括我的我治疗我的治疗目标不充分接受抗VEGF疗法。该提议的目的是审问分子 ANGPTL4通过最终目标促进剩余血管过度渗透性的机制设计新颖的治疗药物来治疗我。