What mechanisms underlie coronary collateral growth?

冠状动脉侧枝生长的机制是什么？

• 批准号: 9220295
• 负责人: WILLIAM M CHILIAN
• 金额: $ 43.54万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9220295
• 关键词: 3-Dimensional; Address; Adenoviruses; Animals; Arteries; Basic Science; Biochemistry; Biology; Blood Vessels; Blood flow; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell; Bypass; CXCR4 gene; Cardiac; Cell Separation; Cells; Collateral Circulation; Confocal Microscopy; Coronary; Coupled; Dimensions; Discipline; Endothelium; Engraftment; Event; Foundations; Gene Expression; Goals; Grant; Growth; Growth Factor; Heart; Home environment; Homing; Image; Incidence; Infarction; Inflammation; Laboratories; Lasers; Measurement; Microscopy; Modeling; Molecular Biology; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Nature; Necrosis; Patients; Physiology; Plasmids; Population; Process; Rattus; Recombinant DNA; Recombinant Proteins; Recruitment Activity; Reporting; Research; Role; Site; Smooth Muscle; Stem cells; Stromal Cell-Derived Factor 1; Sudden Death; Techniques; Tissues; Work; base; chemokine; cytokine; experience; fluorescence imaging; improved; in vivo; in vivo imaging; loss of function; outcome forecast; paracrine; premature; programs; reconstruction; regenerative; response; stem cell fate; therapeutic angiogenesis; two-photon

The purpose of this grant is to define the role of endogenous stem cells in coronary collateral growth. This problem is significant because patients with ischemic heart disease, who have well developed collaterals show a lower incidence of sudden death, have smaller infarcts in the event of an occlusion, and demonstrate a better prognosis than patients with poorly developed collaterals. Currently, there is no evidence (pro or con) that endogenous stem cells are even involved in coronary collateral growth. One goal of the present application is to rectify this deficiency by establishing if stem cells participate in coronary collateral growth and then the mechanisms underlying this effect. Within this context we propose three aims. In the first aim, we will determine the factors produced by the myocardium and coronary vasculature that induce homing and reprogramming of bone marrow stem cells. In this aim, we will define which factors that are produced by the heart and/or growing vasculature activate stem cell homing to the heart and coronary collateral vasculature. Studies will be performed to examine gain and loss of function of 4 key factors to establish their roles in this adaptive, important process. We also will determine if these factors also induce reprogramming of bone marrow in addition to their effects of homing. Reprogramming is used in this context to suggest that these factors will increase the population of sub-classes of bone marrow cells that are committed to a vascular differentiation program. In the second aim, we will determine if stem cells that are recruited to the heart or to the growing vasculature are essential for the process of collateral growth. We will first establish the sub-types of stem cells that home to the heart and coronary vasculature. Then will we study if depletion or enrichment of these cells (during the creation of the chimeric model) will blunt or magnify, respectively, coronary collateral growth. After we have established the type of stem cells that are critical for coronary collateral growth, our studies will focus on the third aim to delineate the fate of the stem cells in the heart by addressing the question: Do they engraft in collateral arteries and differentiate into smooth muscle or endothelium? The overarching goal of these studies is to fill the current void in our understanding about the role of endogenous stem cells in the growth of coronary collaterals. If coronary collateral growth could be stimulated it would theoretically obviate the need for a bypass as a collateral is “nature’s bypass.” Our overall approach is to use the experience of diverse research team in many disciplines—physiology, vascular biology, in vivo imaging, biochemistry, molecular biology—to address this problem.

这笔资助的目的是确定内源干细胞在冠状动脉侧枝生长中的作用。 这个问题很重要，因为患有缺血性心脏病的患者的络脉发育良好 猝死发生率较低，发生闭塞时梗死面积较小，并且表现出 目前，没有证据（赞成或反对）。 内源干细胞甚至参与冠状动脉侧枝生长。 该应用的目的是通过确定干细胞是否参与冠状动脉侧枝生长来纠正这一缺陷 在此背景下，我们提出了三个目标。 确定心肌和冠状动脉血管系统产生的诱导归巢和归巢的因素 骨髓干细胞的重编程为此目的，我们将定义哪些因子是由骨髓干细胞产生的。 心脏和/或正在生长的脉管系统激活干细胞归巢到心脏和冠状动脉侧支脉管系统。 将进行研究来检查 4 个关键因素的功能获得和丧失，以确定它们在此过程中的作用 我们还将确定这些因素是否也会诱导骨骼的重新编程。 骨髓除了归巢的影响外，在这种情况下还使用了重编程来表明这些。 因素将增加致力于血管的骨髓细胞亚类的数量 在第二个目标中，我们将确定干细胞是否被招募到心脏或组织中。 生长的脉管系统对于侧枝生长的过程至关重要，我们将首先建立子类型。 然后我们将研究心脏和冠状脉管系统的干细胞是否耗尽或富集。 这些细胞（在嵌合模型的创建过程中）将分别钝化或放大冠状动脉侧枝 在我们确定了对冠状动脉侧枝生长至关重要的干细胞类型后， 研究将重点关注第三个目标，即通过解决以下问题来描述心脏干细胞的命运： 问题：它们是否植入侧支动脉并分化为平滑肌或内皮细胞？ 这些研究的首要目标是填补目前我们对内源性基因作用的理解空白。 如果冠状动脉侧枝生长能够被刺激，那么干细胞就会参与冠状动脉侧枝的生长。 理论上，不需要旁路，因为抵押品是“自然旁路”。 多个学科的多元化研究团队的经验——生理学、血管生物学、体内成像、 生物化学、分子生物学——来解决这个问题。