Extrinsic and intrinsic signals regulate the temporal and spatial expression of genes that are essential for normal heart development. The results in the precisely orchestrated expression of both intracellular and extracellular components that are characteristic of the heart. The coordinate expression of these genes results in the formation of a normal heart while the aberrant expression may result in malformation of the heart. Significant among the extracellular signals are components of the extracellular matrix (ECM) and growth factors which regulate both proliferation and growth of the myocytes. Receptors for both growth factors and ECM components play a integral role in the regulation of cardiac development. While there are multiple growth factors that can have regulatory effects in vivo, their coordinate expression with specific ECM receptors, integrins, must be first assessed in vitro in order to understand the mechanism(s) that regulate cellular growth and development. The proposed investigations will address the hypothesis that Platelet Derived Growth Factor receptor (PDGFr) subtypes are differentially expressed on myocytes and fibroblasts and when stimulated by the different isoforms of PDGF affect the expression of integrins, which in turn alters ell adhesion and migration. To address this hypothesis, we will examine the following specific aims: 1) To determine the temporal and spatial expression of cardiac defects at the cellular level in the PDGFr and ligand transgenic mice; 2) To manipulate the expression of PDGF receptors and integrins in vitro to determine the affect of altered expression on growth and function of myocytes and fibroblasts; 3) To perform return of function experiments in vitro using adenovirus containing constructs and cells isolated from PDGF receptor knockout mice; and 4) To modulate the expression of PDGF receptors and integrins in whole embryo cultures to determine their role in cardiac development. These experiments will, for the first time determine the role of PDGF isoforms and receptor subtypes in cellular processes, such as myofibrillogenesis, cell adhesion and migration, that are essential to normal cardiac development.
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