Characterization of embryonic stem cell-derived hematopoietic stem cells

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DESCRIPTION (provided by applicant): A 5-year plan is proposed in which the candidate will establish herself as an independent investigator in Stem Cell biology and further our understanding of hematopoietic stem cells generated by embryonic stem cells (ESC-HSC). In graduate school, the candidate developed an expertise in adult stem cells, focusing on HSC. As a postdoc, she furthered her expertise by researching the differentiative potential of ESC, initially exploring the role of the Cdx genes in hematopoietic development from ESC. This work is currently under review for publication. Her current research focuses on ESC-HSC. Although HSC were recently generated from ESC, nothing is known about their phenotype and function, especially in relation to in vivo HSCs. The candidate will test the hypothesis that ESC-HSC are akin to a developmentally immature in vivo HSC compartment by elucidating the phenotype of the ESC-HSC and comparing these cells functionally, by in vivo transplantation assays of HSC activity, and molecularly, via microarray analysis of global gene expression, to HSC purified from mice at different stages of in vivo development. This work will be conducted in the Division of Hematology/Oncology at Children's Hospital Boston under the mentorship of Dr. George Daley, a leader in stem cell biology. The Division is home to multiple laboratories renowned for their achievements in stem cell research (e.g. Drs. Stuart Orkin and Len Zon) and is a rich and collaborative atmosphere for advancing this field. To secure herself as an independent investigator and successfully complete the proposed work, the candidate must 1) expand her expertise in new fields pertinent to her research (e.g. Developmental Biology), 2) acquire new technical expertise (e.g. embryo dissection), and 3) develop the skills necessary to transition to an independent position (e.g. grantsmanship). Towards this end, after extensive consultation with her primary mentor, she has developed a personalized program composed of didactic and practical coursework, seminars and workshops, and a committee of experienced faculty who will meet with her semi-annually to guide her research and career development. The execution of this program, and the research aims outlined in this proposal, will allow the candidate to develop the expertise to establish herself as an independent and competitive investigator in ESC research. PUBLIC HEALTH RELEVANCE: Bone marrow transplantation (BMT) is extensively exploited for the treatment of hematopoietic maladies. Yet, many patients lack donors or must utilize non-ideal donors, resulting in life-threatening complications. Alternative sources of transplantable cells would greatly expand access to this life-saving procedure and minimize complications. Embryonic stem cells, with their capacity to generate any cell type, represent one hope for deriving an alternative cell source for BMT. The work out-lined in this proposal will significantly advance goal by increasing our understanding of cells isolated from embryonic stem cells.