Mechanisms of neovascularization in response to ischemia

缺血反应的新生血管形成机制

• 批准号: 9086396
• 负责人: Victoria L Bautch
• 金额: $ 37.57万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9086396
• 关键词: Adaptor Signaling Protein; Architecture; Arteriosclerosis; Binding; Blood typing procedure; Cardiovascular Diseases; Cardiovascular Physiology; Cell Proliferation; Cell physiology; Cells; Cholesterol; Collagen; Complex; Coupled; Data; Development; Disease; Endothelial Cells; Environment; Fluorescence; Fluorescence Resonance Energy Transfer; Glean; Growth; Health; Hindlimb; Image Analysis; In Vitro; Inflammation; Integrins; Ischemia; KDR gene; Lead; Ligation; Liquid substance; Mechanics; Mediating; Modeling; Molecular; Mus; Patients; Perfusion; Peripheral Vascular Diseases; Positioning Attribute; Process; Protein Deficiency; Proteins; Proteomics; Publishing; Recovery; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Structure; Testing; Therapeutic; Tissues; Transgenic Mice; Trees; Tyrosine Phosphorylation; Vascular remodeling; Work; Wound Healing; angiogenesis; base; blood group; blood perfusion; clinically relevant; femoral artery; gene therapy; hemodynamics; hypercholesterolemia; improved; in vitro Model; in vivo; insight; mutant; neovascularization; novel; oxidized low density lipoprotein; postnatal; protein activation; receptor; repaired; research study; response; restoration; shear stress; small molecule; therapeutic development

DESCRIPTION (provided by applicant): Neovascularization in response to ischemia is an important repair process, which is severely compromised in the setting of chronically elevated cholesterol. Therapeutic neovascularization trials have revealed dramatically reduced responses in hypercholesterolemic patients; however, there is little information on the effects of hypercholesterolemia on arteriogenesis. Arteriogenesis, the outward remodeling of collateral vessels that form bridges between arterial networks, is critical for recovery of blood perfusion to the ischemic tissue after occlusion. Collateral remodeling is driven by a sudden increase in hemodynamic forces, especially shear stress, resulting from the drastic increase in flow through collaterals. This increase in shear stress is sensed by mechanosensory proteins expressed in endothelial cells (ECs), which initiate signal transduction pathways that induce processes such as cell proliferation and inflammation. Despite significant efforts to increase collateral growth and perfusion recovery in the setting of ischemia using small molecules and gene therapy approaches, results have been largely disappointing, underscoring the importance of studies on understanding the molecular mechanisms that drive arteriogenesis. Recently published work from our group, coupled with nascent observations provided in this application, identify the signaling protein adaptor protein Src homologous and collagen protein (Shc) as an essential regulator of neovascularization. To better understand the role of Shc in neovascularization, three interrelated aims are proposed. Aim 1 will determine the role of Shc in neovascularization in response to ischemia in the setting of hypercholesterolemia. Aim 2 will determine the role of Shc in endothelial mechanotransduction under defined collateral hemodynamic conditions in vitro. Aim 3 will determine the molecular determinants in Shc that facilitate neovascularization. Experiments proposed in this proposal will contribute to our understanding of molecular mechanisms of arteriogenesis and collateral remodeling. Elucidation of some of the signals that regulate post-ischemic neovascularization is needed in order to develop therapeutic strategies for diseases such as peripheral vascular disease, arteriosclerosis and wound healing.

描述（由申请人提供）：响应缺血的新血管形成是一个重要的修复过程，在慢性升高胆固醇的情况下，该过程受到严重损害。治疗性新血管化试验显示，高胆固醇患者的反应大幅度降低。但是，关于高胆固醇血症对动脉生成的影响的信息很少。动脉生成是形成动脉网络之间形成桥梁的侧支血管的外部重塑，对于恢复血液灌注至关重要 阻塞后缺血组织。侧支重塑是由于血液动力学力，尤其是剪切应力的突然增加而驱动的，这是由于侧支流动的急剧增加而导致的。在内皮细胞（ECS）中表达的机械感觉蛋白（EC）启动信号转导途径，从而诱导诸如细胞增殖和炎症等过程的信号转导途径来感知剪切应力的增加。尽管使用小分子和基因治疗方法在缺血的情况下增加了附带生长和灌注恢复的巨大努力，但结果基本上令人失望，强调了研究对驱动动脉生成的分子机制的研究的重要性。最近发表了我们小组的工作，再加上本应用程序中提供的新生观察结果，确定信号蛋白衔接蛋白蛋白SRC同源物和胶原蛋白（SHC）作为新生血管的必不可少的调节剂。为了更好地了解SHC在新血管形成中的作用，提出了三个相互关联的目标。 AIM 1将在高胆固醇血症的情况下确定SHC在局部缺血中的作用。 AIM 2将确定SHC在体外定义的侧支血液动力学条件下的作用。 AIM 3将确定SHC中促进新血管形成的分子决定因素。该提议中提出的实验将有助于我们理解动脉生成和侧支重塑的分子机制。为了制定诸如外周血管疾病，动脉硬化和伤口愈合等疾病的治疗策略，需要阐明一些调节缺血后新血管化的信号。