Protease-Mediated Vascular Instability in Development and Disease

发育和疾病中蛋白酶介导的血管不稳定性

• 批准号: 10376738
• 负责人: Courtney T Griffin
• 金额: $ 84.45万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-06 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376738
• 关键词: Area; Award; Blood Vessels; Cell Death; Dangerousness; Data; Development; Disease; Edema; Embryonic Development; Endothelial Cells; Endothelium; Extracellular Matrix Degradation; Genetic Models; Health; Hemorrhage; Inflammation; Knowledge; Life; Mediating; Mission; Mus; National Heart, Lung, and Blood Institute; Pathology; Peptide Hydrolases; Phenotype; Prevention; Proteolysis; Public Health; Publishing; Research; Research Personnel; Research Support; Role; Rupture; Signal Transduction; Site; Therapeutic; Thrombosis; Tissues; United States National Institutes of Health; Vascular Diseases; Work; angiogenesis; blood damage; genetic approach; in vivo; lymphatic vessel; new therapeutic target; postnatal; scaffold

PROJECT SUMMARY/ABSTRACT Vascular integrity is critical for the prevention of tissue edema, thrombosis, inflammation, and hemorrhage. Identifying new factors that influence vascular integrity positively or negatively can provide important therapeutic options for maintaining vascular health. Over the last decade, my lab has taken unbiased genetic approaches in mice to generate vascular phenotypes and to discern their mechanistic causes, and we have seen a powerful theme emerge from our work: excessive proteolysis is detrimental to endothelial cells and to vascular integrity in vivo. Although proteases are well recognized for regulating sprouting angiogenesis in new vessels, there is still a gap in knowledge about their impact on the endothelium of established vessels. Therefore, the objective of this NHLBI Emerging Investigator Award is to define the contexts and the mechanisms through which proteases damage blood and lymphatic vessel integrity. We will approach this broad objective by expanding on two research areas that are supported by our published and preliminary data. First, we will examine extracellular matrix degradation in the context of protease-mediated vascular damage. We will exploit our multiple genetic models with elevated protease activity to reveal commonalities in matrix composition and fragmentation near sites of vascular rupture, and we will seek to discern the relative importance of matrix scaffolding versus matrix/endothelial cell signaling in maintaining vascular integrity in vivo. Secondly, we will focus on protease-mediated endothelial cell necroptosis. Necroptosis is a newly-identified form of cell death, and little is known about its causes or effects in the vasculature. Our preliminary data indicate that proteases can directly trigger endothelial cell necroptosis during embryonic development. We will examine the mechanism through which this occurs and will determine the contribution of protease-mediated necroptosis to various postnatal vascular diseases. The proposed research is paradigm-shifting because it considers new roles for proteases in the context of vascular integrity and because it could generate new therapeutic targets for pathologies associated with high protease activity and vascular fragility.

项目总结/摘要 血管完整性对于预防组织水肿、血栓形成、炎症和出血至关重要。 识别积极或消极影响血管完整性的新因素可以提供重要的 维持血管健康的治疗选择。在过去的十年里，我的实验室已经采取了无偏见的遗传 方法在小鼠中产生血管表型，并辨别其机械原因，我们有 从我们的工作中看到了一个强有力的主题：过度的蛋白水解对内皮细胞有害， 体内血管完整性。虽然蛋白酶被公认为调节新生血管的萌芽， 虽然它们对血管内皮细胞的影响在认识上仍有差距，但它们对已建立的血管内皮细胞的影响仍有差距。 因此，这个NHLBI新兴研究者奖的目标是定义背景和 蛋白酶破坏血液和淋巴管完整性的机制。我们会处理这个问题 通过扩展我们已发表和初步数据支持的两个研究领域，实现广泛的目标。 首先，我们将研究蛋白酶介导的血管损伤中细胞外基质的降解。 我们将利用蛋白酶活性升高的多种遗传模型来揭示基质中的共性， 组成和破碎的血管破裂的网站附近，我们将寻求辨别的相对 基质支架与基质/内皮细胞信号传导在维持体内血管完整性中的重要性。 其次，我们将重点关注蛋白酶介导的内皮细胞坏死性凋亡。坏死性上睑下垂是一种新发现的 这是一种细胞死亡的形式，关于它在脉管系统中的原因或影响知之甚少。我们的初步数据 表明在胚胎发育过程中蛋白酶可直接触发内皮细胞坏死性凋亡。我们将 检查发生这种情况的机制，并确定蛋白酶介导的 坏死性凋亡与各种产后血管疾病有关。拟议的研究是范式转变，因为它 考虑了蛋白酶在血管完整性方面的新作用，因为它可以产生新的 与高蛋白酶活性和血管脆性相关的病理学的治疗靶点。