The long-term goals of this proposal are to understand the mechanisms and roles of focal adhesion kinase (FAK) and its signaling pathways in the cardiovascular system. FAK is a cytoplasmic tyrosine kinase that plays a key role in integrin-mediated signal transduction pathways as well as in signal transduction by growth factor receptors including those that play critical regulatory roles in the cardiovascular system. Consistent with these results from in vitro studies FAK gene knockout in mice resulted in an embryonic lethal phenotype with major defects in the axial mesodermal tissues and cardiovascular system. Despite the abundant knowledge of FAK interaction with other proteins and its roles in cell signaling in vitro, still relatively little is known about the in vivo Functions of FAK in embryonic development or in the adult organisms. Although the FAK total knockout mice suggested a potential role for FAK in the cardiovascular system, the embryonic lethality made it not very useful for studies on the role of FAK in cardiovascular development or functions in the adult animal. To overcome the problem of embryonic lethality of the FAK total knockout mice, we have generated FAK floxed mice with the FAK gene flanked by two loxP sites in preliminary studies. We have also generated transgenic mice with FAK transgene expression in the endothelial cells (ECs) and obtained transgenic mice with specific expression of Cre recombinase in ECs or cardiomyocytes. In this application, Aim 1 will investigate the role of FAK in ECs in [vasculogenesis and angiogenesis by breeding the FAK/IoxP mice with the TIE2-Cre mice to create EC-specific FAK knockout mice and examine the effects on vasculogenesis and angiogenesis in the embryo and in adult mice.
Aim 2 will study molecular and cellular mechanism of FAK function in ECs by crossing the FAK conditional knockout mice with transgenic mice expressing FAK or its mutants and by isolating ECs from these mice to examine FAK interaction with other proteins, intracellular signaling pathways and cellular functions including migration and proliferation.
Aim 3 will determine the role and mechanism of FAK in cardiac development and function by crossing FAK/loxP mice with cardiomyocyte specific Cre mice to generate heart specific FAK conditional knockout mice and analyzing the effects on the development and function of the heart. These studies will generate not only significant insights into the physiological function of FAK signaling pathways in vivo but also critical information for potential new therapies for pathological alterations in tumor angiogenesis and cardiac hypertrophy and heart failure.
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