| Project/Area Number |
16390275
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | Osaka University (2006-2007)
Kanazawa University (2004-2005) |
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Principal Investigator |
TAKAKURA Nobuyuki Osaka University, Research Institute for Microbial Diseases, Professor (80291954)
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| Co-Investigator(Kenkyū-buntansha) |
UENO Masaya Osaka University, Research Institute for Microbial Diseases, Assistant Professor (20334766)
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| Project Period (FY) |
2004 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥15,140,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥840,000)
Fiscal Year 2007: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2006: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2005: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2004: ¥5,900,000 (Direct Cost: ¥5,900,000)
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| Keywords | hematopoietic stem cell / self-renewal / galectin-3 / PSF1 / PSF1 / 血管内皮細胞 / SLD5 / TIE2 / Psf1 / apelin |
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| Research Abstract |
Quiescence is thought to be one of important feature of hematopoietic stem cells (HSCs) for the prevention of exhaustion in bone marrow (BM) adult hematopoiesis. Recently, it has suggested that HSCs change their cell cycle status from cycling population to quiescent one between 3 and 4 weeks after birth. However, the precise molecular mechanism of induction in quiescence of HSCs is not fully understood. Although Tie2, a receptor tyrosine kinase expressed on HSCs has been suggested to regulate quiescence of HSCs, its role is not clearly known. Therefore, we isolated molecules affected by Tie2 activation and analyzed the function of those molecules. We isolated a novel evolutionarily conserved DNA replication factor, PSFI (Partner of SLD5-1) in HSCs. In one-year-old PSF1(+/-) mice, the pool size of stem cells and progenitors is decreased. While young PSF1(+/-) mutant mice develop normally, are fertile, and have no obvious differences in hematopoiesis in the steady state compared with wild-type mice, intravenous injection of 5-fluorouracil (5-FU) is lethal in PSF1(+/-) mice due to a delay in induction of HSC proliferation during ablated BM reconstitution. Our data indicated that PSF1 is required for acute proliferation of HSCs in the BM of mice. Moreover, we found that galactose binding lectin-3 (galectin-3; Gal-3) upregulated by Tie2 activation plays a role in quiescence of HSCs. HSCs from mice harboring conditionally overexpressed Gal-3 under the control of the Tie2 promoter progressed slowly through the cell cycle because of induction of p21. By contrast, cell cycle of Tie2+HSC population from Gal-3-deficient mice was accelerated resulted in exhaustion of HSCs possessing long-term repopulating ability in adult BM. These indicated that Gal-3 is negative regulator of HSC cycling and has a crucial role in inhibition of exhaustion for adult hematopoiesis.
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