Fas and Fas Ligand in the Development of the Hematopoietic System: A Grant Proposal

Abstract

Bone marrow failure is a condition that blocks normal hematopoiesis. Instead of producing functional blood and immune cells, bone marrow cells either cease to produce blood and immune cells altogether or, in some cases, produce non-functional cells in mass quantities, a condition known as leukemia. In the experiments described below, we seek to understand the basic mechanisms of normal hematopoiesis. It has been demonstrated that the death receptor Fas has non-apoptotic functions, including cell proliferation. In hematopoietic cells, Fas expression level does not correlate with susceptibility to Fas-mediated apoptosis. In T-lymphocytes, ligation of FasL, a typical inducer of cell death, has been shown to engage in reverse signaling that has stimulatory consequences on the cells. In HSPCs it is unknown whether reverse signaling from FasL or non-apoptotic Fas signaling occurs and is biologically relevant. Taken together, these observations support the hypothesis that: Fas and FasL, via autocrine stimulation, play a crucial role in the survival and proliferation of HSPCs during the establishment of a homeostatic hematopoietic system, Further insight into h e normally developing hematopoietic system can shed light on and improve the prognosis and treatment of bone marrow failure associated diseases. Specifically, discoveries from this proposed study can be translated to a wide variety of fields incuding bone marrow transplantation as well as cancer treatment and prevention.