The candidate's long term objective is to study cardiovascular disease utilizing models of genetically manipulated mice. Training in internal medicine and cardiovascular medicine has provided the candidate with useful clinical insights to direct basic research. Past experience as a Research Fellow in the Cardiology Branch of the National Institutes of Health provided useful initial training in molecular based biological research. The candidate is currently performing research in the Cardiovascular Research Institute at the University of California, San Francisco (UCSF) focusing on thrombosis related research. The candidate's research proposal will define the sources and roles of circulating tissue factor (TF) and the roles of TF expressed by various cell types. Recent studies have revealed that TF plays a critical role in vascular development, hemostasis, and inflammation. Most TF-deficient mouse embryos die at midgestation with failed vascular development. The candidate has developed a mouse line in which TF, the primary initiator of coagulation, is expressed transgenically under the control of the smooth muscle cell alpha actin promoter. Two approaches will be used to develop mouse models of cell specific gene inactivation. In the first approach, the candidate will attempt to rescue the TF null phenotype with the trangenic mouse line described earlier. The second approach will utilize tissue-specific cre recombinase-mediated excision of a floxed allele. These mice will be used for the following specific aims: 1. Determine whether TF expression in vascular smooth muscle cells is sufficient to support embryonic development and hemostasis. 2. Determine whether circulating TF, monocyte TF, smooth muscle or endothelial TF are necessary for hemostasis and/or thrombosis. 3.Determine whether circulating TF, monocyte TF, smooth muscle or endothelial TF are important for inflammation. Shaun Coughlin, the candidate's mentor, and David Phillips, a member of the Advisory Committee, are very familiar with the mouse models of thrombosis that will be used in the specific aims. Additionally, Steve Young, another member of the Advisory Committee and a physician-scientist, is experienced in generating and studying genetically modified mice. The diversity of resources makes UCSF is an ideal setting to train physican scientists.
