The Role of Intrinsic and Extrinsic Factors in Megakaryocytic-Erythroid Progenitor Lineage Commitment

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PROJECT SUMMARY Candidate. Dr. Scanlon, a member of an underrepresented minority, is a third year postdoctoral fellow in the Department of Laboratory Medicine at Yale School of Medicine with degrees in Molecular Cell Biology, Diagnostic Genetic Sciences, and Biomedical Science. She is an experimental biologist looking to expand her ability to utilize algorithms and perform bioinformatic analyses with the long-term goal of becoming an independent investigator. Her previous training and work with intracellular signaling pathways controlling progenitor cell response to injury combined with her current work in hematopoiesis uniquely qualify her to conduct the proposed work. The proposed career development plan will build upon her previous training and enhance her path toward independent research. This plan includes experimental and didactic learning in image processing, bioinformatic analysis, algorithm optimization, and advanced statistical analyses to independently analyze massive quantities of data. Development in these areas will ready her for independent academic molecular and cell biology research in the current era. Mentor/Advisors and Environment. Dr. Scanlon's primary mentor, Diane Krause, MD, PhD, and imaging advisor, Dr. Joerg Bewersdorf, PhD will guide Dr. Scanlon through the proposed training and research activities. In addition to Dr. Krause's extensive experience in mentoring numerous successful academic researchers, and her expertise in hematopoietic stem and progenitor cells, and Dr. Bewersdorf expertise in high quality live imaging, Dr. Scanlon will also receive bioinformatic analysis support and learn cell-tracking algorithms through established collaborations with Dr. Masahiko Sato, developer of cell-tracking algorithms, and Mr. Rolando Garcia-Millian, a dedicated bioinformatic support specialist at Yale. Dr. Scanlon will meet regularly with her mentor, advisor, and collaborators to ensure her progress. The proposed career development plan utilizes the expertise and rich resources available at Yale to delineate additional training activities to facilitate Dr. Scanlon's research. Research. The molecular mechanisms underlying lineage commitment of hematopoietic stem and progenitor cells have implications in deriving blood cells in vitro for transfusion medicine, as well as elucidating aberrant pathways responsible for hematological disorders. Dr. Scanlon's recent postdoctoral work has focused on studying lineage commitment of Megakaryocytic-Erythroid Progenitors (MEPs). Previous work in the lab identified MYB (a transcription factor) to be important in controlling human MEP fate, however the mechanism remains elusive. She proposes to use live imaging to directly visualize MEPs undergoing lineage commitment, as well as transcriptomic and epigenomic approaches to tease apart the mechanism by which MYB regulates this process. Additionally, she will launch an independent line of studies investigating the effect of intercellular signaling between MEP and other marrow-residing cells on MEP fate. The results of these studies may shed light on more general rules of stem and progenitor fate decisions, as well as potentially help derive patient-specific platelets and red blood cells for transfusions. This career development award will be an instrumental step in Dr. Scanlon's trajectory towards an independent investigator and leader in hematopoiesis.!