The long-term objectives of this project are to determine the mechanisms by which erythropoietin (EPO) contributes to the control of the proliferation and differentiation of erythrocytes. Our efforts have focused on the identification of the biochemical consequence of Epo receptor activation and assessing the role of these responses in the various cellular responses including promoting cell cycle progression, suppression of apoptosis and differentiation. We have demonstrated that Epo induce the activation of a variety of signaling pathways, including the activation of the transcription factors Stat5a and Stat5b, but that these functions are dispensable including the activation of the transcription factors Stat5a and Stat5b, but these functions are dispensable based on studies with receptor mutants. To extend these observations, the first specific aim will assess the requirement for these functions in the broadest physiological terms in erythropoiesis. This will be accomplished by deriving mice that express various Epo receptor mutants that have lost the ability to activate various pathways. These mutant strains will be further used to determine whether the distal region of the Epo receptor mediates functions that are redundant to the minimally essential, membrane proximal region of the receptor. One of the critical functions mediated by Epo receptor activation of Jak2 is the induction of genes that are required for the expression of Bcl-X/L as well as other genes. In the second specific aim we proposed to focus on the identification and characterization of a specific group of immediately early genes in the Epo response. For these studies. mutants will be used that contain the minimal receptor required for function. Differential expression, cloning approaches will be used to identify the genes induced. Two genes have been identified in preliminary studies and their function, as well as genes to be identified, will be assessed for function by deriving strains of mice that lack the genes. Together the studies will provide new insights into the critical biochemical functions that are induced by Epo that are essential for hematopoiesis.
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