This proposal describes a 5 year training program for the development of an academic career in pulmonary medicine. The principal investigator has completed a clinical and research fellowship in pulmonary and critical care medicine at Boston University and will continue his training in a basic science pulmonary laboratory. During this training program, the principal investigator will be mentored by an experienced lung epithelial scientist, Dr. Alan Fine, while drawing on the consulting expertise of Dr. Peter J. Quesenberry, a leader in stern cell biology. The program is focused on the potential of bone marrow stem cells to serve as progenitors of lung epithelium. The research proposal reviews recent work in Dr. Fine's laboratory demonstrating that cultured bone marrow-derived cells injected into bleomycin-injured mice, are able to engraft in the injured lung epithelium as differentiated type I pneumocytes. This finding has broad implications for the therapy of lung diseases involving the alveolar epithelium, such as ARDS. However, cultured marrow cells are a heterogeneous population of several cell subtypes and whether one or all of these subtypes can serve as alveolar epithelial precursors is not known. Furthermore, the state of differentiation of the key lung-engrafting marrow cell is not clear, and how these bone marrow cells evolve into a lung epithelial phenotype remains uncertain. The principal investigator proposes a series of experiments designed to address these fundamental issues. The research proposal's specific aims include: 1) Identifying marrow cell sub-populations that can reconstitute the alveolar epithelium during bleomycin-induced lung injury; 2) Characterizing the gene expression profile of these sub-populations; and 3) Examining the in vivo differentiation of marrow cells into alveolar type I cells. The unique research training environment at the Boston University Pulmonary Center and the program proposed provides the principal investigator with the opportunity to meet the objectives of this proposal and to develop a career in academic medicine focused on the biology and therapy of lung disease.
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