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.
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