The overall objective of this proposal is to provide post-doctoral training while at the same time testing the hypothesis that regulation of protein phosphatase 2A (PP2A) by a novel upstream signaling pathway involving p21 activated kinase (Pakl) is an important element coordinating the state of phosphorylation of important contractile regulatory proteins, including cTnl, MyBP-C, and PLB. Specific Aim #1 is to determine the levels of phosphorylation of cTnl, MyBP-C, and PLB in isolated rat cardiac ventricular myocytes following activation of the Pak1 pathway by the agonists bradykinin (BK) and lysophosphatidic acid (LPA) or by adenoviral-mediated over-expression of Pak1. In Specific Aim #2 the functional changes in myofilament response to Ca2+ and the dynamics of intracellular Ca2+, and shortening are examined as a result of the changes in protein phosphorylation state in myocytes generated in Aim #1. Specific Aim #3 is to measure the activity of PP2A in cardiomyocytes and co-localization with Pak1. Together these data will provide evidence for a novel pathway of activation of PP2A and a role for concomitant regulation of contractile and intracellular Ca2+ handling.
NIH ExPorter
NIH ExPorter