Calcium Dependent Gene Expression in Muscle

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DESCRIPTION (provided by applicant): This proposal describes a four-year training program for an academic career in molecular cardiology. The principal investigator has completed clinical training in internal medicine residency as well as clinical cardiology with additional training in heart failure/transplantation. He has also completed two additional years of post-doctoral work in the laboratory of the sponsor, R. Sanders Williams, M.D. During this time the principal investigator has developed fundamental skills in molecular biology and cellular physiology in order to establish a program focusing on calcium imaging in myocytes. The Mentored Clinical Scientist Development Award is an excellent opportunity to further his scientific development under Dr. Williams. The sponsor is the Dean of Duke Medical School in Durham, NC and an expert in cardiac and skeletal muscle biology. He has successfully mentored numerous molecular cardiologists, post-doctoral fellows and graduate students and junior faculty members over the years. This program will build on the extensive training initiated over the last two years and focus on calcium signaling and transcriptional activation in models of muscle hypertrophy and specialization. Work in the Williams' laboratory has established the link between neural activation of gene expression and the calcium regulated serine-threonine phosphatase, calcineurin. Loss of function and gain of function studies have established the calcineurin pathway as a critical nodal point for excitation transcription coupling. Research in this program will focus on the proximal aspects of the calcineurin pathway in order to understand calcium activation and identify upstream aspects of this pathway in muscle. Specific aims will include: 1) to determine the spatial and temporal aspects of calcium signaling that regulate calcineurin and NFAT signaling in isolated single fibers and cardiomyocytes, 2) to define the calcium signals responsible for NFAT activation in an intact animal, 3) to identify calcium signaling molecules that are differentially expressed among specialized myofiber subtypes and are important in gene regulation. The research proposed will establish a better understanding of calcium signaling and its influence on cardiac and skeletal myopathies. The training environment established in the Division of Cardiology at Duke University has demonstrated a continued commitment to the career development of young faculty, particularly in molecular cardiology.