Molecular mechanisms involved in regulation of lineage choice decisions during granulopoiesis
Friday 23 January 2009
Prof.dr. Paul Coffer and dr. Miranda Buitenhuis
Project
Hematopoiesis is a complex series of events which results in the formation of all blood lineages. The development of mature blood cells is regulated at various levels, including self-renewal of pluripotent stem cells in the bone marrow, proliferation of progenitors and differentiation of hematopoietic stem cells to mature blood cells. Aberrant regulation of hematopoiesis can lead to severe clinical conditions ranging from myeloproliferative disorders to severe immune deficiencies. In order to develop novel therapies against illnesses caused by aberrant regulation of hematopoiesis, it is necessary to understand the molecular mechanisms underlying these processes. Cytokines, stromal cells and extracellular matrix proteins play an important in regulation of hematopoiesis. Recently we have demonstrated that the PI3K/PKB signal transduction pathway plays a critical role in regulation of lineage choice decisions during myeloid development: inhibition of PKB is required for eosinophil maturation, whereas activation of PKB is necessary to induce neutrophil differentiation. Since PKB is regulated by both G-CSF and IL-5, additional signals must be involved in down-regulation of PKB activity during eosinophil differentiation. Co-culture of hematopoietic progenitors with stromal cells induces eosinophil but not neutrophil development, suggesting that stromal cells might play an important role in inhibition of PKB activity during eosinophil differentiation.
Research project:
This project aims to investigate which intracellular signal transduction pathways are activated upon interaction of stromal cells with hematopietic progenitors leading to eosinophil maturation. Upon identification of these signal transduction pathways, retroviral transduction experiments will be performed on human hematopoietic progenitors in order to investigate whether eosinophil and neutrophil differentiation are differentially regulated by these proteins.
Techniques
Cell culture, (immuno)histochemistry, molecular biological techniques
Duration
6 or 9 months
Contact
Dr. Miranda Buitenhuis, m.buitenhuis@umcutrecht.nl, 088 75 535 68
Dr. Kristin Denzer, k.denzer@umcutrecht.nl, 088 75 576 73
More info
UMC website - Dept. of Immunology
Molecular immunology website
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