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Myocardial Regulation of betaARK1 by Protein Kinase C

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This proposal describes a 5 year training program for development as an independent clinician-scientist. I have completed residency training in General Surgery which included a 2 year NIH-funded research fellowship in molecular cardiovascular biology. I then completed a residency program in Thoracic Surgery and am now an Assistant Professor in the Section of Cardiothoracic Surgery at the University of Cincinnati. This program will build upon my scientific foundation in G protein-coupled receptor signaling in heart disease. Arnold Schwartz, PhD will mentor my scientific and career development as he is a leader in the area of cardiac signal transduction and has an outstanding record of training young investigators. To enhance the training, Stephen B. Liggett, MD will serve as a co-mentor and is an expert in cardiac beta-adrenergic receptor (betaAR) signaling. In addition, an advisory committee of highly-regarded investigators will provide scientific and career advice. Molecular mechanisms for the transition from compensatory or adaptive myocardial hypertrophy to heart failure remain unclear. This research plan focuses on defining cross-talk between signaling pathways in the heart which are critical for the development of myocardial hypertrophy (Gq-coupled receptor signaling) and the regulation of cardiac function (betaAR signaling). The betaAR kinase (betaARK1) is the most abundant G protein-coupled receptor kinase in the heart and is critical in the regulation of betaAR signaling and cardiac function. Protein kinase C (PKC), which is activated in the development of hypertrophy following stimulation of Gq-coupled receptors, has been shown to phosphorylate and activate betaARK1 in vitro. This proposal will directly test the central hypothesis that there is cross-talk between myocardial PKC activity and betaAR signaling which occurs at the level of betaARK1 in vivo. The consequences of the actions of PKC on betaARK1 lead to the impaired betaAR signaling and cardiac function associated with ventricular hypertrophy. Based on the intellectual and scientific environment, the commitment from my Department, and support from my mentors and advisory committee, I believe the University of Cincinnati Cardiovascular Research Center provides an ideal setting for training physician-scientists to become successful independent investigators.
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