The long term goal of the proposed studies is to understand the signal transduction mechanisms in the development and functions of the cardiovascular system. The previous funding period focused on the role of focal adhesion kinase (FAK) in endothelial cells (ECs) in vasculogenesis and angiogenesis as well as in cardiac myocytes in heart development and function by using Cre-loxP mediated conditional knockout (KO) of FAK in ECs and cardiomyocytes. Analysis of the EC-specific FAK conditional KO mice established a critical role for FAK in angiogenesis and vascular development during embryogenesis in vivo. Furthermore, we showed that deletion of FAK in the isolated primary ECs led to multiple defects including reduced cell survival and migration which may be responsible for the defective angiogenesis and vascular development in vivo. Analysis of the cardiomyocyte-specific FAK conditional KO mice suggested a role of FAK in the regulation of cardiac hypertrophy. In addition, we generated a mouse KO for FIP200 (FAK-family interacting protein of 200 kDa) to understand its functions in vivo. We found that inactivation of FIP200 gene resulted in mid/late-gestational embryonic lethality caused by heart failure and liver lesions. Analysis of the FIP200 KO mice suggested that alterations in TSC-mTOR and TNFa signaling pathways leading to changes in cell size and apoptosis in the heart and liver may be responsible for the developmental abnormality and embryonic lethality in FIP200 KO mice. Despite the progress suggesting important functions of FAK and FIP200 in the cardiovascular development and functions, the role of specific signaling pathways regulated by FAK and FIP200 has not been examined in the context of cardiovascular development in vivo. Based on our previous and preliminary studies, we propose to 1.) analyze the FAK signaling pathways in the regulation of EC migration, invasion and angiogenesis using isolated primary ECs, 2.) determine the role of FAK signaling pathways in angiogenesis and vascular development in vivo by using mouse knock-in approaches, and 3.) investigate the mechanisms of FIP200 regulation of TSC-mTOR and TNFa signaling pathways in cardiac development using a combination of cell and molecular biology approaches in isolated cardiomyocytes and genetic interaction studies of various relevant KO mice. Relevance: These studies will generate significant insights into the mechanisms of signal transduction by FAK and FIP200 in the cardiovascular system in vivo and may also provide critical information for potential development of novel therapies for cardiovascular diseases. ? ? ?
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