Molecular Dissection of Cardiac Conduction System Development

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DESCRIPTION (provided by applicant): This proposal describes a tailored basic research training program for the transition from post-doctoral fellow to independent investigator. The principal investigator has completed a structured residency training program in Internal Medicine with the intent to complete clinical fellowship training in Cardiology. The proposal described herein will foster a command of transcriptional regulation of cardiac development and disease. In this regard, Dr. Eric Olson, the chariman of Molecular Biology at the University of Texas at Southwestern and a world's authority in the field, will serve as the ideal mentor. He has trained numerous post-doctoral fellows in the past and has sponsored previous and current physician-scientists. Furthermore, a scientific advisory committee has been proposed that will not only provide regular constructive criticism of data, hypotheses, and proposed experiments but invaluable advice regarding career development as an independent and productive physician-scientist. It is also expected that members of the advisory committee will be invaluable in offering their expertise and unique reagents to foster the proposed research plan. The research will focus on elucidating the molecular mechanisms underlying development and maturation of the cardiac conduction system. Recent work in the Willecke and Olson laboratories has established that the connexin 30.2 (Cx30.2) gene is a valuable marker for the developing atrioventricular and sinoatrial nodes. The proposed experiments will build on this observation to advance our knowledge about conduction system form and function using the mouse as a model system to study human development and disease. The specific aims include the following: 1) Define the Cx30.2 gene regulatory elements required for proper conduction system development, 2) Isolate and manipulate Cx30.2+ conduction cells by creating novel genetic tools and techniques, and 3) Analyze the cell autonomous role of GATA4 in cardiac conduction system development. The Molecular Biology and Cardiology departments will provide the ideal interdisciplinary setting not only to conduct the proposed experiments but to develop as an independent clinician-scientist. RELEVANCE (See instructions): The cardiac conduction system coordinates the heart's normal rhythm, and its dysregulation contributes to arrhythmogenesis. Given that embryonic gene expression programs are often re-deployed during disease states, understanding development of the cardiac conduction system may someday shed light on arrhythmia pathophysiology and possibly pave the way for novel anti-arrhythmic drug discovery.