The Role of ADAM15 in sTie2 shedding in Ischemic Angiogenesis

ADAM15 在缺血性血管生成中 sTie2 脱落中的作用

• 批准号: 7751014
• 负责人: Daniel Corey
• 金额: $ 5.26万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-30 至 2010-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7751014
• 关键词: Adam15 gene; Angiopoietin-1; Angiopoietin-2; Angiopoietins; Binding; Blood Vessels; Blood capillaries; Cardiovascular Diseases; Cells; Clinical Research; Congestive Heart Failure; Disease; Disintegrins; Endothelial Cells; Engineering; Extracellular Domain; Family; Fiber; Fibroblasts; Growth Factor; Human; Hypertension; Hypoxia; Ischemia; Isolated limb perfusion; Ligands; Limb structure; Maintenance; Measures; Mediating; Mediator of activation protein; Membrane; Messenger RNA; Metalloproteases; Molecular; Mus; Muscle; Muscle Fibers; Pathologic Neovascularization; Pathway interactions; Patients; Peptide Hydrolases; Perfusion; Peripheral arterial disease; Phenotype; Phosphatidylinositols; Phosphotransferases; Physiological; Plasma; Play; Pre-Clinical Model; Process; Production; Protein Tyrosine Kinase; Proteins; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Recovery; Role; Serum; Skeletal Muscle; Small Interfering RNA; System; Testing; Time; Vascular Endothelial Growth Factors; Vascular remodeling; Wild Type Mouse; Work; angiogenesis; capillary; density; in vitro testing; in vivo; insight; overexpression; receptor; receptor binding; response; retinal angiogenesis; vessel regression

DESCRIPTION (provided by applicant): Tie2 is an endothelial receptor tyrosine kinase (RTK) that is required for physiological and pathological angiogenesis. The ligands for Tie2, the Angiopoietins, have context-dependent effects on angiogenesis and vascular maintenance. Recent evidence suggests that metalloprotease-mediated shedding of a soluble Tie2 {sTie2) protein regulates the Tie2/Ang system, although the mechanisms of its production and function are not known. In humans, sTie2 is detectable in the serum of healthy control subjects, and it is increased in disease states associated with vascular regression, such as congestive heart failure and hypertension, suggesting a potential anti-angiogenic function for sTie2. Consistent with these findings, overexpression of an engineered soluble Tie2 protein blocks both physiological and pathological angiogenesis in preclinical models. sTie2 shedding from endothelial cells is induced by VEGF and is dependent on the phosphoinositide (PI) 3-kinase/Akt pathway. Furthermore, plasma concentrations of sTie2 and VEGF are significantly increased in patients with the most severe manifestation of peripheral arterial disease (PAD). These findings suggest that sTie2 modulates the angiogenic response. The effector protease responsible for Tie2 cleavage has not previously been identified, although the primary candidate mediators of sTie2 shedding are the ADAM (a disintegrin and metalloprotease) proteins. ADAM15 has been shown to be required for pathological angiogenesis, and preliminary studies in this proposal will demonstrate that ADAM15 is required for sTie2 shedding from endothelial cells. To date, the role of elevated sTie2 in CLI and other disease states is not known, and whether ADAM15 is involved in sTie2 shedding in vivo remains unclear. In this proposal, we hypothesize that ADAM15 is the principal protease for Tie2 cleavage in endothelial cells and that ADAM15-induced sTie2 is required for ischemic angiogenesis. To test this hypothesis, the Specific Aims of this proposal are to: 1) Identify the role of ADAM15 in sTie2 shedding and the molecular mechanism of ADAM15 activation; and 2) Determine the requirement for ADAM 15 in ischemic angiogenesis in vivo. Accomplishing these Specific Aims will provide key insights into the mechanisms regulating sTie2 shedding as well as its role in ischemic angiogenesis such as in PAD.

描述(申请人提供)：Tie2是一种内皮受体酪氨酸激酶(RTK)，是生理和病理血管生成所必需的。Tie2的配体，血管生成素，在血管生成和血管维持方面具有上下文依赖性的作用。最近的证据表明，金属蛋白酶介导的可溶性Tie2(STie2)蛋白的脱落调节Tie2/Ang系统，尽管其产生和功能的机制尚不清楚。在人类中，sTie2在健康对照组的血清中可检测到，在与血管退化相关的疾病状态下，如充血性心力衰竭和高血压，sTie2会增加，这表明sTie2具有潜在的抗血管生成功能。与这些发现一致的是，在临床前模型中，过表达工程可溶性Tie2蛋白可以阻止生理性和病理性血管生成。血管内皮细胞分泌sTie2依赖于磷脂酰肌醇(PI)3-激酶/Akt信号转导通路。此外，在外周动脉疾病(PAD)表现最严重的患者中，血浆sTie2和VEGF浓度显著升高。这些发现表明，sTie2调节血管生成反应。尽管sTie2脱落的主要候选介体是ADAM(一种去整合素和金属蛋白酶)蛋白，但导致Tie2裂解的效应蛋白尚未被鉴定。ADAM15已被证明是病理性血管生成所必需的，本提案中的初步研究将证明ADAM15是从内皮细胞中脱落sTie2所必需的。到目前为止，升高的sTie2在CLI和其他疾病状态中的作用尚不清楚，ADAM15是否参与体内sTie2的脱落仍不清楚。在这个方案中，我们假设ADAM15是内皮细胞中Tie2裂解的主要蛋白酶，并且ADAM15诱导的sTie2是缺血血管生成所必需的。为了验证这一假说，这一提议的具体目的是：1)确定ADAM15在sTie2脱落中的作用和ADAM15激活的分子机制；2)确定ADAM15在体内缺血血管生成中的需求。实现这些特定的目标将为调控sTie2脱落的机制以及它在PAD等缺血性血管生成中的作用提供关键的见解。