This proposal establishes a five year plan for Dr. William Slayton to develop the skills and experience needed to be a successful clinician/scientist in the field of Pediatric Hematology/Oncology. Currently, Dr. Slayton has completed 1 year of clinical fellowship and 2.5 years of mentored research. Dr. Slayton has a strong interest in developmental hematopoiesis, and completed 15 months in the lab of Dr. Robert Christensen, defining the role of cytokines in neutrophil and macrophage development in the human fetus. He relocated to Salt Lake City to work in the laboratory of Dr. Gerald Spangrude, where he has spent the last 11 months devising techniques to isolate megakaryocyte progenitors from mouse bone marrow. Dr. Slayton'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. Slayton's long-term career goal is to become an independent investigator capable of combining the discipline of developmental hematology with issues in clinical hematology, leukemogenesis, and bone marrow transplantation. Dr. Slayton's research project is based on the hypothesis that the megakaryocytic and erythroid lineages separate from the myeloid and lymphoid lineages early in the hematopoietic hierarchy. This hypothesis is based on the observations in the Spangrude laboratory of a progenitor population that reconstitutes lymphoid and macrophage lineages, but fails to reconstitute erythrocytic and megakaryocytic lineages, and is supported by the behavior of progenitors in the fetal liver, several knockout models, and several tumor cell lines. The Spangrude lab has established all of the assays necessary for this study. Enriched populations of multipotent progenitor cells will be isolated using a cell sorter based on expression of cell surface markers and mitochondrial stains. Cell behavior will be defined in vitro through tissue culture studies, and in vivo through transplantation experiments. Finally, these enriched populations will be used to produce cDNA libraries, which will be used to study the expression of genes known to be involved in hematopoietic commitment, as well as used in differential expression and microarray assays to look for the expression of novel genes. Dr. Spangrude's laboratory provides an excellent environment for Dr. Slayton to carry out this proposal. A research advisory committee that meets the NIH requirements has been guiding Dr. Slayton's research progress. In this rich and supportive environment, Dr. Slayton will gain the experience necessary to contribute to the understanding of the early cellular and molecular events in megakaryopoiesis.
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