Characterization of regulators of hemotopoietic stem cell homeostasis

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Hematopoietic stem cells (HSCs) give rise to each of the definitive blood lineages found in the adult vertebrate. Runxl is required for definitive HSC specification during embryogenesis and regulates adult HSC homeostasis. I recently performed a chemical genetic screen for modifiers of runx1+ HSC formation in zebrafish and identified the prostaglandin pathway as a conserved vertebrate regulator of HSCs. A stable prostaglandin E2 (PGE2) derivative was found to be a potent inducer of both zebrafish and murine HSCs and is currently being developed for use in human clinical trials for ex vivo expansion of HSCs prior to transplantation. To further characterize mechanisms controlling HSC induction in the vertebrate embryo, I plan to examine the interaction of the wnt and prostaglandin pathways in HSC formation in the AGM. I hypothesize that the prostaglandin pathway regulates wnt mediated induction of HSCs in the embryo and in adult HSC homeostasis. To characterize the role of the wnt pathway in HSC formation, I will use several heatshock inducible transgenic zebrafish lines that express activators or repressers of wnt signaling. Through chemical manipulation as well as morpholino oligonucleotide (MO) knock-down of PGE2 production, I will test how prostaglandin signaling can enhance or suppress wnt mediated HSC formation and determine the conservation of this interaction in adult marrow and human cord blood HSC homeostasis. Taken together, these studies will enhance our understanding of the mechanisms regulating HSC formation and homeostasis. Stimulation of these pathways may prove beneficial for the treatment of patients with hematological disorders, bone marrow failure or in recovery after transplantation, while pathway inhibition might be useful in the treatment of leukemia. A K01 award will aid me in achieving my goal of becoming an independent scientist in an academic setting studying the regulation of HSC induction and function. RELEVANCE (See instructions): Hematopoietic stem cells form the foundation of our blood and immune system; the formation and function of these cells are carefully controlled in the body. The proposed research will help to identify mechanisms that regulate the birth and propagation of these stem cells. This work has great relevance for the development of novel agents to regulate leukemia, and for recovery from chemotherapy and bone marrow transplant.