| Project/Area Number |
16590925
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
EMA Hideo The University of Tokyo, Institute of Medical Science, Project Associate Professor, 医科学研究所, 産学官連携研究員(特任助教授) (50344445)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Hematopoietic stem cells / Self-renewal / Signal transduction / Wnt / β-catenin / Stem cell factor / Thrombopoietin / Lnk |
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| Research Abstract |
Hematopoietic stem cells (HSCs) undergo self-renewal, multilineage differentiation, or apoptosis. However, how their fate is determined is poorly understood. Supposedly, HSCs are regulated by extracellular stimuli and are also protected from the stimulation in their specific niches where they normally reside in vivo. As not much is known of niche factors that play a role in the regulation of HSCs, we have attempted to identify such factors. We and others have shown that stem cell factor and thrombopoietin (TPO) play a crucial role as a positive regulator and that transforming growth factor β1 does so as a negative regulator. Secreted proteins that belong to the Wnt family have been candidate niche factors. We purified Wnt 3a protein to examine its direct effect on normal HSCs. Although it was difficult to obtain highly purified such a protein, a sample enriched in Wnt3a protein was tested for its biological activity on purified mouse HSCs. Our Wnt protein turned out to be ineffective f
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or induction of HSC division. Enforced expression of an activated form of β-catenin was also ineffective for the induction. These data suggest that whether Wnt3a is a self-renewal factor for HSCs should be carefully reevaluated. In addition, expression analysis suggested that Wnts may be more important during the development of HSCs than in the steady state of adult HSC regulation. We have recently focused on intracellular signaling molecules influential for HSC fate decision. We have successfully invented immunostaining methods to analyze signal transduction in a very limited number of primary cells by confocal microscopy and laser scanning cytometry. By making use of mutant mice deficient in the adaptor protein Lnk, we have shown that Lnk interferes the probability of HSC self-renewal via TPO signal transduction pathways. Particularly, a combination of Jak/STAT and Akt phosphorylation and p38 MAPK dephosphorylation was suggested to be associated with self-renewal in HSCs. We have also shown that β-catenin can be activated by TPO signal in HSCs. We are currently interested in its role in cytokine signaling. Less
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