The extracellular matrix is connected to the intracellular cytoskeleton at focal adhesion sites via integrin transmembrane receptors. One tyrosine protein kinase which as been shown to be associated with integrin clustering is pp125FAK (FAK). The present research proposal is designed to test the hypothesis that the integrin-pp125FAK (FAK). The present research proposal is designed to test the hypothesis that the integrin-pp125FAK tyrosine protein kinase complex is the receptor responsible for lead dependent changes in cardiac gene expression.
The specific aims of this research are 1) to determine FAK protein, FAK phosphorylation, and FAK immunolocalization in contracting and quiescent cultured neonatal and adult ventricular myocytes and to correlate these data to mRNA levels of b-MHC, ANF, and SERCA2, 2) to determine whether the inhibition of FAK phosphorylation will affect the expression of these genes, and 3) to determine whether the activity of the ANF promoter can be modulated by either overexpressing FAK which has been shown to inhibit FAK phosphorylation. Understanding the mechanisms responsible for mechanochemical signal transduction in cardiac myocytes will allow for a better understanding of how the myocardium adapts or fails to adapt to an increased load.
