SIGNAL TRANSDUCTION THROUGH TH ERYTHROPOIETIN RECEPTOR

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DESCRIPTION (Applicant's Description): Erythropoiesis is a highly regulated developmental process during which pluripotent hematopoietic progenitor cells become committed to differentiate into erythroid precursors in response to erythropoietin and other growth factors. The presence of erythropoietin and c-Kit receptors is critical for this process to occur normally. It is not known, however, whether these receptors specifically "instruct" progenitor cells to differentiate along a particular lineage or if they merely allow the cells to survive long enough so they can then differentiate along a stochastic program. This application seeks to address this issue in the physiological setting of the whole mouse, utilizing embryonic stem cell technology as well as the use of retroviruses to infect primary hematopoietic progenitors. The role of apoptosis will be examined by looking at the effect of expression of various a n ti-apoptotic genes such as Bcl-2, Bcl-x, CrmA, and c-IAPs on the differentiation of BaF3 and HCD-57 cell lines in addition to progenitors derived from fetal livers. Tandem mass spectrometry based protein sequencing approaches (MALDI-MS/MS) will be utilized to identify signaling molecules that a s s ociate with the EpoR when it is activated by Epo. Since the m o lecular/developmental defect in several red cell disorders such as polycythemia vera and erythroleukemias is not yet known, it is likely that these studies will lead to identification of molecules that may be defective in these diseases or provide insights into the developmental abnormality that leads to bone marrow hyperplasia. Finally, the nature of the signaling defect in polycythemia vera will be studied. It will be determined if the hyperresponsiveness of hematopoietic cells to Epo results from altered expression patterns or mutations affecting the function of negative modulators of signaling such as SH-PTP1 and CIS (Cytokine Inducible SH2 domain).