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: 7253226
• 负责人: Clarence M. Findley
• 金额: $ 4.23万
• 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/7253226
• 关键词: Adenoviruses; Affect; Amputation; Angiopoietin-1; Angiopoietin-2; Angiopoietins; Antibodies; Apoptosis; Area; Arteries; Atherosclerosis; Biology; Blood Vessels; Blood flow; Bromodeoxyuridine; Cardiovascular Diseases; Cell Proliferation; Clinical; Complex; Cutaneous; Data; Development; Disease; Elderly; Embryo; Endothelial Cells; Exercise; Exertion; Extracellular Domain; Hindlimb; Image; Immunohistochemistry; Immunoprecipitation; Impairment; In Situ Nick-End Labeling; Ischemia; Lasers; Lead; Ligands; Ligation; Limb structure; Mediating; Modeling; Molecular; Morphogenesis; Mucous Membrane; Mus; Mutation; Necrosis; Numbers; Nutrient; Oxygen; Pain; Pathologic Neovascularization; Pathway interactions; Patients; Perfusion; Peripheral; Physiological; Population; Process; Regulation; Research Personnel; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Skin; Staining method; Stains; System; TIE-2 Receptor; Tissues; Transgenic Mice; Ulcer; Vascular Diseases; Vascular blood supply; Vascular remodeling; Venous Malformation; Western Blotting; age effect; age related; angiogenesis; claudication; density; experience; femoral artery; gastrointestinal; insight; malformation; man; migration; mouse model; mutant; novel; novel therapeutics; older patient; programs; response; therapeutic angiogenesis; therapeutic target

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(申请人提供)：外周动脉疾病(PAD)对老年人的影响不成比例。在其极端形式下，PAD会导致组织缺血、坏死、溃疡和截肢，这是临床上已经受到影响的人群。然而，到目前为止，还没有有效的治疗PAD的方法。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身上变得迟钝，旨在增强血管生成反应的药物治疗可能被证明是有效的。Tie2与血管生成素 是胚胎和出生后血管生成的重要组成部分。Tie2信号和Tie2信号的调节 功能复杂，其配体血管生成素-1(Ang1)和血管生成素-2(Ang2)对血管系统具有相反的作用。Ang1促进血管成熟和稳定，而Ang2促进血管失稳，促进血管生成和血管重塑。我们小组的最新数据 证明了Tie2信号对运动诱导的骨骼肌血管生成的需求，而骨骼肌也是PAD中治疗性血管生成的相同靶组织。虽然已经发现了Tie2的天然高激活突变体，但它们矛盾地导致血管重塑和血管畸形，而不是促进血管生成。综上所述，这些观察表明Tie2是一个潜在的促血管生成治疗靶点，并暗示了高激活突变体在血管重塑过程中的不稳定作用，但对激活突变导致的Tie2信号通路和下游细胞反应的变化知之甚少。我们假设Tie2信号是缺血性血管生成所必需的，并且Tie2激活突变部分通过激活血管失稳和血管重塑所需的信号通路和细胞反应来扰乱血管形态发生。因此，本研究的具体目的是：(1)研究R849W激活突变对Tie2信号转导的影响；(2)研究TE R849W激活突变对Tie2介导的内皮细胞反应的影响；(3)确定Tie2在缺血性血管生成中的需求及血管生成的年龄依赖性损伤。