What mechanisms underlie coronary collateral growth?

这项资助的目的是确定内源性干细胞在冠状动脉侧支生长中的作用。这 这个问题很重要，因为患有缺血性心脏病的患者， 猝死的发生率较低，在闭塞的情况下梗死较小，并证明 侧支循环发育不良的患者预后更好。目前，没有证据（赞成或反对） 内源性干细胞甚至参与了冠状动脉侧支的生长。当前的一个目标 应用是通过确定干细胞是否参与冠状动脉侧支生长来纠正这一缺陷， 那么这种效应背后的机制。在此背景下，我们提出了三个目标。在第一个目标中，我们将 确定由心肌和冠状血管系统产生的诱导归巢的因子， 骨髓干细胞的再编程。在这个目标中，我们将定义哪些因素是由 心脏和/或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，以检查4个关键因素的功能获得和丧失，以确定它们在其中的作用。 适应性强的重要过程我们还将确定这些因素是否也诱导骨重编程 除了它们的归巢作用之外。在这种情况下，重编程被用来表明这些 这些因素将增加骨髓细胞亚类的数量，这些细胞被定向到血管内皮细胞， 差异化方案在第二个目标中，我们将确定干细胞是否被招募到心脏或 血管系统的生长是侧枝生长过程的关键。我们将首先建立子类型 心脏和冠状血管系统的干细胞。然后我们将研究是否耗尽或富集的 这些细胞（在嵌合模型的产生过程中）将分别钝化或放大冠状动脉侧支 增长在我们确定了对冠状动脉侧支生长至关重要的干细胞类型后， 研究将集中在第三个目标，通过解决心脏干细胞的命运， 问：它们是否植入侧支动脉并分化为平滑肌或内皮？的 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。 干细胞在冠状动脉侧支生长中的作用。如果能够刺激冠状动脉侧支的生长， 从理论上讲，需要一个旁路作为抵押品是“自然的旁路”。我们的总体方法是使用 在生理学、血管生物学、体内成像等多个学科中， 生物化学、分子生物学来解决这个问题。

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.