Molecular basis of cardiac homeostasis

心脏稳态涉及一组复杂的生理覆盖系统。任何一个系统的异常都可能导致相关平行系统的缺陷，并导致包括血管生成、血液凝固、血管张力和细胞粘附异常在内的表型。在目前的拨款提案中，我们选择研究心脏稳态的各个方面，这些方面在分子水平上仍然没有明确的定义。在第一个目标中，我们将剖析控制心脏血管生成活性肝素的肝素分子和生物合成途径。本研究的中心假设是硫酸肝素生物合成途径作为开关，在不同的生物位点增强或抑制生长因子与生长受体的相互作用。我们所有的生物站点。我们的总体目标是确定硫酸肝素生物合成途径中调控硫酸肝素生物合成途径精确结构的基因，以及在调节关键调控生长因子和生长因子受体相互作用中的硫酸肝素精确结构及其特异性生物学效应。在第二个目标中，我们将描述Flk-1和Tie-2启动子的DNA元件，这些启动子负责在构成条件下介导心脏内皮细胞特异性表达，并响应血栓形成和血管生成。这一目标的中心假设是Tie-2和Flk- 1基因在心脏中受血管床特异性机制的调节。我们的总体目标是确定基础状态和心脏病发作后心脏特异性表达的转录基础。在第三个目标中，我们将开始研究内皮细胞在介导心脏稳态中的不同功能之间的关系。这一目的的中心假设是，一个生理系统的异常可能刺激或抑制心功能的改变。最后一个目的的总体目标是表征内皮细胞功能在介导心脏血管系统的两种表型，即血栓形成和血管生成的等级顺序。我们将重点研究四个具有代表性的基因：TM、P选择素、alphavbeta3和eNOS。虽然这三个目标侧重于不同的研究领域，但它们代表了维持正常心脏功能的关键重叠控制点。目前的拨款提案的总体目标是了解是了解稳态系统是如何在分子水平上协调调节心脏的。事实上，我们推测这些系统中的一个或多个分子异常是许多尚不清楚的多效性心脏病的基础。此外，这些区域中的每一个都构成了药物治疗的新靶点，将对心功能产生广泛的有益影响。

Cardiac homeostasis involves a complex set of physiologically overlaid systems. Abnormalities in any one system may result in defects in the linked parallel systems and result in phenotypes that include abnormalities in angiogenesis, blood coagulation, vascular tone, and cell adhesion. In the current grant proposal, we have chosen to study various aspects of cardiac homeostasis, which remain poorly defined at a molecular level. In the first aim, we will dissect the heparan molecular and biosynthetic pathway(s) that control(s) the production of angiogenically active heparan in the heart. The central hypothesis of this aim is that the heparan sulfate biosynthetic pathway functions as switch to enhance to suppress growth factor-growth receptor interactions at different biological sites. Our overall biological sites. Our overall goal is to pinpoint the genes within the heparan sulfate biosynthetic pathway, which regulate the precise structure of heparan sulfate biosynthetic pathway, which regulate the precise structure of heparan sulfate and their specific biologic effects in modulating critical regulating growth factor and growth factor receptor interactions. In the second aim, we will delineate DNA elements of the Flk-1 and Tie-2 promoters that are responsible for mediating cardiac endothelial cell-specific expression under constitutive conditions and in response to thrombosis and angiogenesis. The central hypothesis of this aim is that the Tie-2 and Flk- 1 genes are regulated in the heart by vascular bed-specific mechanisms. Our overall goal is to identify the transcriptional basis of cardiac-specific expression in the basal state and after heart attacks. In the third aim, we will begin to examine the relationship between different functions of the endothelial cell in mediating cardiac homeostasis. The central hypothesis of this aim is that abnormalities in one physiological system may either stimulate or suppress alterations in cardiac function. The overall goal of this last aim is to characterize the hierarchical order of endothelial cell function in mediating two phenotypes of the cardiac vasculature, namely thrombosis and angiogenesis. We will focus on four representative genes: TM, P selectin, alphavbeta3 and eNOS. While the three aims focus on distinct areas of research, they represent critical overlapping control points for maintaining normal cardiac function. The overall goal of the current grant proposal is to understand is to understand how homeostasis systems are coordinately regulated in the heart at a molecular level. Indeed, we speculate that molecular abnormalities in one or more of these systems underlie many poorly understood pleiotropic cardiac diseases. Furthermore, each of these areas constitutes a novel target for drug therapy that will have widespread beneficial effects on cardiac function.