This proposal describes a five-year program for the further development of the candidate's career as an academic vascular surgeon and towards attaining independent status as an investigator in cardiovascular disease. The candidate is currently an Assistant Professor in Vascular Surgery with a basic foundation in vascular biology research. The proposed work will be performed with strong institutional support in an environment that includes an outstanding basic research program in cardiovascular biology. The research will be performed within the Pacific Vascular Research Laboratory at UCSF, under the mentorship of Dr. Didier Stainier, a leader and expert in cardiovascular development and stem cell biology. The proposed research will study the role of bone marrow-derived progenitor cells in neovascularization of the ischemic hindlimb. Critical limb ischemia is a major clinical problem, and current therapies are often unable to prevent gangrene and amputation. There is mounting evidence that bone marrow-derived progenitor cells contribute to neovascularization of ischemic tissues. The scientific aims of this proposal will test the hypothesis that bone marrow-derived progenitor cells are necessary for revascularization of the ischemic hindlimb and that specific progenitor cell subpopulations are most capable of promoting neovascularization in vivo. The proposed experiments will utilize available knockout mice and models of both hindlimb ischemia and neovascularization of Matrigel implants in vivo. The specific aims include: 1) determination if endothelial progenitor cells are necessary for revascularization of the ischemic hindlimb, using Id1Id3-/- mice which have impaired mobilization of endothelial progenitor cells; 2) determination if myeloid progenitor cells are necessary for hindlimb revascularization, using lethally irradiated mice reconstituted with fetal liver cells derived from colony stimulating factor receptor-1 -/- mice; and 3) determination of which subpopulations of bone marrow or circulating progenitor cells are capable of supporting neovascularization using an in vivo model of progenitor cell-dependent angiogenesis. By defining the role of progenitor cells in neovascularization, this proposal will support the development of novel cellular and molecular therapies for patients with vascular disease.