IP3 RECEPTOR MEDIATED APOPTOSIS DURING MYOGENESIS

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DESCRIPTION (Adapted from applicants' abstract) The applicant received a Ph.D. in cell physiology and, after clinical medicine and cardiology training, began post-doctoral work in molecular biology. This MCSD award will support mid-to-later stages of post-doctoral training in molecular and cell biology to allow for his transition to an independent investigator. The Division of Circulatory Physiology at Columbia-Presbyterian Medical Center has committed 90% of his time to basic science research. The goal of this application is to advance the understanding of the molecular signal transduction pathways that govern embryologic muscle development, specifically apoptosis. The overall working hypothesis is that embryonic development of striated muscle requires the predetermined elimination of primordial somites and myoblasts that is mediated, in part, via the IP3 receptor. Work is planned to begin during the term of the award and continue through independence of the investigator. Studies by the mentor have shown that IP3 receptors are expressed in striated muscle cells and also play a critical role in T cell apoptotic signaling. Prior studies by the applicant and mentor note: 1) Apoptosis within developing somites and maturing myocytes in vivo; 2) The ability to label the myogenic lineage via a novel homeodomain protein; 3) An increase in IP3 receptor density within somites and interdigital regions prone to apoptosis; and 4) Overexpression of IP3 receptors in myoblasts causes inhibition of cell fusion in vitro. These data suggest a causal relationship between IP3 receptor expression and incipient myoblast differentiation and apoptosis. Therefore, the specific aims of this project are designed to test the hypotheses that: 1) Myogenesis involves an ordered pattern of apoptosis in somites and limbs, 2) IP3 receptors of somitic and interdigital limb myoblasts define primordial cells and maturing myoblasts, respectively, destined to undergo apoptosis; and 3) IP3 receptors are important determinants of intracellular calcium which regulates myogenic differentiation and apoptosis. The elucidation of this network will further the understanding of striated muscle developmental regulation and the fate of apoptotic myoblasts. Dr. Skopicki will be mentored by Dr. Andrew Marks, the Director of Molecular Cardiology and an expert in muscle cell transcription and molecular biology. The College of Physicians and Surgeons of Columbia University affords an outstanding academic environment for training in both basic scientific theory and experimentation.