This proposal describes a 5-year training program for development of an academic career in pediatric cardiology. The candidate has completed a residency in pediatrics, a fellowship in pediatric cardiology, and is currently completing a Howard Hughes Medical Institute Postdoctoral Fellowship for Physicians. The Mentored Clinical Scientist Development Award is uniquely suited to promote the career development of the candidate as she transitions from postdoctoral fellow to junior faculty at a university medical center, and will allow the candidate to build on her strong biochemical background to acquire intellectual grounding and technical expertise in mouse genetics and developmental biology. This training will aid the candidate in merging her clinical and research interests to become an independent investigator in the field of cardiovascular developmental biology. The research plan is designed to define the role of the heterotrimeric G protein G-alpha13 (Ga13) in vascular development. Ga13 mediates signaling from a variety of G-protein-coupled receptors and is required for blood vessel development and survival of mouse embryos. To test the hypothesis that Ga13 signaling in endothelial cells is important for normal blood vessel development and vascular integrity, and to probe the role of Ga13 signaling pathways in endothelial cell function and vascular and embryonic development, the candidate will: 1) use an endothelial-specific Ga13 transgene to attempt to rescue the vascular defects of Ga13-/-embryos, 2) use Cre-lox technology to create and analyze mice with endothelial-specific deletion of Ga13, and 3) analyze Ga13 deficient endothelial cells isolated from endothelial knockout mice in a variety of in vitro assays to determine the contribution of Ga13 signaling to cellular behaviors crucial for normal vascular development, such as chemotaxis and tube formation. The environment at UCSF's Cardiovascular Research Institute will expose the candidate to cutting-edge research in cell signaling and cardiovascular development. The sponsor, Dr. Shaun Coughlin, is a physician-scientist with an exceptional record of developing young careers and initiating basic research programs with important clinical applications. The advisory committee of Drs. Henry Bourne, Didier Stainier, and Zena Werb are leaders in the field of G protein signaling, cardiovascular development, and vascular biology, and are uniquely qualified to advise the candidate as well.
