This proposal establishes a five year plan for Dr. Christopher R. Cogle to develop the skills and experience needed to become a successful clinician-scientist in the field of Hematology/Oncology. Currently, Dr. Cogle has completed one year of clinical fellowship and two years of mentored research under the direction of Dr. Edward W. Scott. In Dr. Scott's laboratory, Dr. Cogle has worked to define the role of human hematopoietic stem cells in remodeling blood vessels and other damaged tissues. Dr. Cogle's immediate goal is to broaden his research skills through a combination of a carefully structured didactic teaching program and completion of a research project in the laboratory of his mentor. Dr. Cogle's long-term goal is to become an independent investigator capable of combining the discipline of stem cell biology with issues in clinical hematology, oncology and bone marrow transplantation. Dr. Cogle's research project is based on the hypothesis that the human hematopoietic stem cell (HSC) can act as a functional hemangioblast, contributing to both hematopoiesis and reparative vasculogenesis. The hypothesis is based on observations in the Scott laboratory where a novel murine model of diabetic retinopathy clearly showed that adult murine HSC act as functional hemangioblasts. In mice receiving single cell HSC transplant and secondary transplants, retinal injury resulted in multiple neovascular tufts derived from donor HSCs. During Dr. Cogle's mentored research fellowship in the Scott laboratory, he established a human HSC xenograft model in NOD/scid mice to test whether human HSC also provide functional hemangioblast activity. Functional transdifferentiation will be defined by confocal microscopy, serial sectioning, immunohistochemistry with multiple markers, and karyotyping. Additionally, vascular tissue samples from female patients having received bone marrow transplantation from male donors will be analyzed for presence of transgender endothelial cells. Ultimately, these results point toward the clinical application of targeting bone marrow-derived endothelial progenitor cells (EPCs) homing to sites of vascular remodeling. Dr. Scott's laboratory provides an excellent environment for Dr. Cogle to carry out this proposal. In this rich and supportive environment, Dr. Cogle will gain the experience necessary to contribute to the understanding of reparative vasculogenesis and stem cell transdifferentiation.
