Project Summary This K08 proposal has been developed to facilitate my career development through coursework, training in professional development, guidance from my mentor as well as my advisory committee, and research training. My background in genomics and cancer susceptibility has led me to pursue additional training in hematopoietic stem cell biology in order to round out my skills in translational research and achieve my long-term goal of becoming an independent investigator and leader in the area of hematopoiesis and leukemia susceptibility. My short-term goal is therefore to pursue additional research training in Dr. John Chute's lab with the aim of increasing understanding of the role of the bone marrow (BM) niche in the hematopoietic stem cell (HSC) functional decline with aging, injury, and leukemogenesis. As HSCs age, they display distinct abnormalities such as skewing toward myeloid differentiation, decreased repopulation ability, and cancer predisposition. Clinically, this corresponds with the increasing incidence of myelodysplasia, myeloproliferative diseases, acute leukemia, as well as adaptive immune system defects. Our lab has demonstrated that BM endothelial cells (ECs) produce epidermal growth factor (EGF) which is capable of markedly accelerating HSC regeneration and overall hematopoietic reconstitution following acute radiation injury. Interestingly, high dose irradiation produced a phenotype of accelerated aging in the hematopoietic system. Therefore, I hypothesize that augmentation of the HSC vascular niche paracrine mechanisms, such as the EGF signaling pathway, can rescue this declining function. The specific aims and approaches are to (1) determine whether EGF treatment is sufficient to reverse HSC aging, using pharmacologic approaches, (2) determine whether cell-specific deletion of EGFR accelerates HSC and immune system aging, using a mouse model which results in a loss-of-function of EGFR on bone marrow stem and progenitor cells, and (3) determine the mechanisms through which EGF reverses HSC aging by testing the effect of EGF on HSC senescence, survival, cell cycle status, and the Ras/MEK/ERK pathway. This is a high-impact, translational proposal that applies state-of-the-art techniques and unique mouse models to characterize the role and mechanism by which EGF rejuvenates aging HSCs. This will provide the basis of a novel role for EGF and has significant translational potential to ameliorate the adverse effects of HSC aging and injury after chemotherapy, radiation therapy, and bone marrow transplantation.