SIGNAL TRANSDUCTION THROUGH TH ERYTHROPOIETIN RECEPTOR

Project: Research project

Project Details

Description

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).
StatusNot started