The Role of the GATA2 Interactome in Erythropoiesis

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PROJECT SUMMARY My goal is to become an exceptional tenure track physician-scientist focused on identifying diverse and unexpected cellular factors and pathways that regulate hematopoiesis, and elucidating the molecular mechanisms of their function. This K08 Mentored Clinical Scientist Research Career Development Award would provide me with the necessary support to complete a rigorous and structured training program and establish myself as a successful independent investigator. My proposed research focuses on the transcription factor GATA2, which is critical for emergence of the blood and bone marrow during development and maintenance of the bone marrow stem cell compartment in adults. Clinically, germline mutations in GATA2 cause the poorly understood GATA2 Deficiency Syndrome. I hypothesize that there is a diverse and undiscovered network of proteins that interface with GATA2 to modulate the process of hematopoiesis. To this end, I have developed uniquely effective and specific anti-GATA2 antibodies that react with mouse and human GATA2 and utilized these to identify 153 putative GATA2 interactors in erythroid precursor cells. In this proposal, I plan to establish how these proteins function in GATA2 biology and in human and mouse erythropoiesis. I am supported in these efforts by a team of accomplished investigators and mentors who constitute my Research Advisory Committee: my primary mentor Dr. Emery Bresnick, an international expert in red cell biology, hematopoiesis and GATA factors; Dr. Igor Slukvin, an international expert on induced pluripotent stem cells and their application for basic and applied science; Dr. Jing Zhang, an internationally recognized expert on malignant hematopoiesis; and Dr. Andreas Friedl, Chair of the UW-Madison Department of Pathology and Laboratory Medicine who has guided my career development and organized my recruitment. I will also enjoy technical support from Dr. Ying Ge, Professor of Cell and Regenerative Biology and Director of the Human Proteomics Program at UW-Madison. These studies have the potential to radically expand our understanding of how a small number of transcription factors accomplish the wide variety of functions necessary to successfully establish and maintain a healthy bone marrow. The results will form the foundation for independent studies and future R01 proposals. The mentoring and career development that I receive during the course of this research will prepare me to excel as a physician- scientist and integrate me into the greater hematology community.