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Projekt
Molekulare Mechanismen Notch vermittelter Zelllinienentscheidungen bei der entwicklung hämatopoetischer Zellen aus adulten und embryonalen Stammzellen
Antragstellerin
Professorin Dr. Ursula Just
Fachliche Zuordnung
Nuklearmedizin, Strahlentherapie, Strahlenbiologie
Förderung
Förderung von 2002 bis 2007
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 5377769
Notch genes encode a highly conserved family of transmembrane receptors that regulate progression of cells from an undifferentiated to a differentiated state as well as cell fate decisions made at branchpoints between distinct developmental pathways. We plan to define the molecular mechanisms that mediate these effects of Notch signalling in adult and embryonic hematopoietic development. Using murine hematopoietic progenitor cell lines in which Notch signalling can be conditionally regulated, we have shown that activated Notch and hematopoietic cytokines act together to direct hematopoietic progenitor cells to differentiate along myeloid lineages. Induction of myeloid differentiation by activated Notch involved the direct and specific activation of the hematopoietic transcription factor PU.1 which regulates myeloid versus lymphoid cell fate outcome. First, we will determine if Notch signalling influences the lineage decision of hematopoietic stem cells between myeloid and B-lymphoid cells by conditionally inducing Notch signalling in primary sorted bone marrow stem cells and embryonic stem cells. Next we will analyse at which level and how Notch signalling interacts with other extrinsic or intrinsic signals. We will test our hypothesis that the different signals are integrated at locus control regions to achieve proper expression levels of transcription factors (PU.1) and of functional genes (globin). Finally, we will determine if Numb, an intracellular protein which antagonizes Notch signalling at binary cell fate decisions, does this also in hematopoietic stem cells.
DFG-Verfahren
Schwerpunktprogramme
