Tie2 Regulation and Role in Pathological Angiogenesis

Tie2 在病理性血管生成中的调节和作用

• 批准号: 7050743
• 负责人: Clarence M. Findley
• 金额: $ 4.35万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050743
• 关键词: angiogenesis; angiopoietins; atherosclerosis; biological signal transduction; blood vessels; cell differentiation; cell migration; cell proliferation; enzyme activity; gene mutation; genetically modified animals; growth factor receptors; immunocytochemistry; immunoprecipitation; ischemia; laboratory mouse; laser Doppler flowmetry; microarray technology; peripheral blood vessel disorder; protein tyrosine kinase; vascular endothelium; western blottings

DESCRIPTION (provided by applicant): Peripheral artery disease (PAD) disproportionately affects the elderly. In its extreme form, PAD results in tissue ischemia, necrosis, ulceration and limb amputation in an already clinically compromised population. To date, however, no effective therapies exist for the treatment of PAD. Angiogenesis is the compensatory physiological response to tissue ischemia and occurs in PAD and other forms of cardiovascular disease. Interestingly, this seemingly protective angiogenic process is blunted in the elderly, and pharmacologic therapies aimed at augmenting the angiogenic response may prove effective. Tie2 and the Angiopoietins are essential components of embryonic and post-natal angiogenesis. Regulation of Tie2 signaling and function is complex, as its ligands, Angiopoietin-1 (Ang1) and Angiopoietin-2 (Ang2), have opposing effects on the vasculature. Ang1 promotes vascular maturation and stabilization while Ang2 promotes vessel destabilization, facilitating angiogenesis and vascular remodeling. Recent data from our group demonstrates the requirement of Tie2 signaling for exercise-induced angiogenesis in skeletal muscle, the same target tissue for therapeutic angiogenesis in PAD. Although naturally occurring hyperactivating mutants of Tie2 have been identified; they paradoxically result in altered vessel remodeling and vascular malformations as opposed to enhanced angiogenesis. Together, these observations implicate Tie2 as a potential pro-angiogenic therapeutic target and suggest a destabilizing role for the hyperactivating mutants during vascular remodeling, however little is known about alterations in Tie2 signaling pathways and downstream cellular responses that occur as a result of the activating mutations. We hypothesize that Tie2 signaling is required for ischemic angiogenesis and that Tie2 activating mutations disrupt vascular morphogenesis in part by activating signaling pathways and cellular responses necessary for vessel destabilization and vascular remodeling. Accordingly, the Specific Aims of this proposal are to: (1) Characterize the effects of the R849W activating mutation on Tie2 signaling (2) Characterize the effects of te R849W activating mutation on Tie2-mediated endothelial cellular responses (3)Determine the requirement forTie2 in ischemic angiogenesis and the age-dependent impairment of angiogenesis.

描述（由申请人提供）：外周动脉疾病（PAD）不成比例地影响老年人。在其极端形式中，PAD在临床上已经受损的人群中导致组织缺血、坏死、溃疡和肢体截肢。 然而，迄今为止，不存在用于治疗PAD的有效疗法。血管生成是对组织缺血的代偿性生理反应，发生在PAD和其他形式的心血管疾病中。 有趣的是，这种看似保护性的血管生成过程在老年人中是迟钝的，旨在增强血管生成反应的药物治疗可能被证明是有效的。Tie 2与血管生成素 是胚胎和出生后血管生成的重要组成部分。Tie 2信号传导的调节和 功能很复杂，因为它的配体血管生成素-1（Ang 1）和血管生成素-2（Ang 2）对血管系统具有相反的作用。Ang 1促进血管成熟和稳定，而Ang 2促进血管不稳定，促进血管生成和血管重塑。我们集团的最新数据 证明了Tie 2信号传导对于骨骼肌中运动诱导的血管生成的需要，骨骼肌是PAD中治疗性血管生成的相同靶组织。尽管已经鉴定了Tie 2的天然存在的超活化突变体，但它们矛盾地导致改变的血管重塑和血管畸形，而不是增强的血管生成。总之，这些观察结果暗示Tie 2作为潜在的促血管生成治疗靶点，并表明在血管重塑过程中过度活化突变体的不稳定作用，然而关于Tie 2信号通路和下游细胞反应的改变所知甚少，这些改变是由于活化突变而发生的。我们假设Tie 2信号传导是缺血性血管生成所必需的，Tie 2激活突变部分通过激活血管不稳定和血管重塑所必需的信号传导途径和细胞反应来破坏血管形态发生。因此，本研究的具体目的是：（1）表征R849 W激活突变对Tie 2信号传导的影响;（2）表征R849 W激活突变对Tie 2介导的内皮细胞反应的影响;（3）确定缺血性血管生成和年龄依赖性血管生成损伤对Tie 2的需要。