? ? This career development award will facilitate the transition of the candidate to independent investigator and physician-scientist within the Division of Cardiovascular Medicine at Stanford University. Through exposure :o a first class scientific environment, interaction with an internationally renowned mentor, and consultation with an outstanding advisory committee, the candidate is expected to broaden his scientific skill set and reach his goal of independence as an integrative cardiovascular biologist in the field of heart failure and cardiac function. The experiments planned build on material already published and aim to test mechanistic hypotheses suggested by the earlier work. The role of apelin-APJ in cardiovascular health and disease was first described by the candidate in 2003. Follow up investigations describing the in vivo physiology of apelin revealed a highly conserved and therapeutically promising neurohormonal system. In the work proposed here, signaling mechanisms by which myocardial APJ receptor binding regulates cardiac contractility and hypertrophy will be identified using a combination of cell culture, isolated myocyte cell shortening and in vivo techniques. The subcellular location of the myocardial APJ receptor, its G protein coupling, and its proximate signaling partners will be explored in order to identify ultimate effector mechanisms (Specific aim 1). The contribution of paracrine, endocrine and autocrine processes to the integrated cardiovascular effects of apelin will be elucidated using tissue specific, conditional gene deletion in mice, in vivo and in co-cultured cells (Specific aim 2). Finally, the role of apelin in cellular energetics will be determined through isolated heart nuclear magnetic resonance spectroscopy and direct measurement of oxidative phosphorylation in skinned muscle fibers (Specific aim 3). The apelin-APJ system is a compelling candidate for pharmacological manipulation in the treatment of heart failure due to positive effects on fluid balance, cardiac load and contractile reserve. The experiments described herein will provide a sound mechanistic basis for the future translation of this body of work to the clinical domain. (End of Abstract) ? ? ?
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