The primary goal of this proposal is to train the principal investigator to become an independent physician-scientist in the field of cardiac stem cell and regenerative biology. He proposes a detailed program of career development and a research plan involving human embryonic stem cell (hESC) derived cardiomyocytes. The training plan includes coursework, conferences, specialized instruction, and formation of an advisory committee to foster career development as a physician-scientist. In preliminary experiments, we demonstrated that grafting of hESC-derived cardiomyocytes into both uninjured and infracted hearts of immunodeficient rats produced human myocardium in vivo. Parallel in vitro work has identified highly promising strategies for deriving enriched cultures of human embryonic cardiomyocytes. The candidate exploits opportunities presented by this work in proposing the following specific aims: 1) optimize implants of hESC-derived myocardium in the infracted rat heart and determine whether this results in improved mechanical function;2) to test the hypothesis that hESC-derived cardiomyocyte grafts will show electromechanical coupling with the adjacent host myocardium;3) to test the hypothesis that with in vivo maturation, grafted hESC-derived myocardium will show phenotypic alterations in excitation-contraction coupling;and 4) develop strategies for the purification and/or induced differentiation of specialized cardiac conduction system cells from hESC-derived cardiomyocytes. The University of Washington represents an outstanding environment both for such studies and for the development of physician-scientists, a situation will be further enhanced through an institutional commitment to establish a Center for Cardiovascular &Regenerative Medicine. Combined with the support of the present career award, this environment will allow the principal investigator to acquire the technical and critical thinking skills to commence a successful independent line of investigation.
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