| Project/Area Number |
14208087
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cell biology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
MIYAZONO Kohei The University of Tokyo, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (90209908)
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| Co-Investigator(Kenkyū-buntansha) |
MIYAZAWA Keiji The University of Tokyo, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (40209896)
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| Project Period (FY) |
2002 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥53,170,000 (Direct Cost: ¥40,900,000、Indirect Cost: ¥12,270,000)
Fiscal Year 2005: ¥11,440,000 (Direct Cost: ¥8,800,000、Indirect Cost: ¥2,640,000)
Fiscal Year 2004: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
Fiscal Year 2003: ¥13,520,000 (Direct Cost: ¥10,400,000、Indirect Cost: ¥3,120,000)
Fiscal Year 2002: ¥15,730,000 (Direct Cost: ¥12,100,000、Indirect Cost: ¥3,630,000)
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| Keywords | TGF-β / angiogenesis / ES cell / BMP / osteoblast / signal transduction / receptor / cell differentiation / 血管内皮細胞 / 平滑筋細胞 |
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| Research Abstract |
1)Flk1-positive vascular progenitor cells derived from mouse ES cells (ESC) are capable of differentiating into mural and endothelial cells in the presence of VEGF. In the presence of both endothelial cells and mural cells in cultute, latent TGF-beta is efficiently activated. We showed that SB-431542, a synthetic molecule that inhibits the kinases of receptors for TGF-beta, facilitated proliferation and sheet formation of ESC-derived endothelial cells. Moreover, SB-431542 up-regulated the expression of claudin-5, an endothelial specific component of tight junctions, suggesting that endogenous TGF-beta signals play important roles in regulating vascular growth and permeability.
2)We showed that osteoblastic differentiation of mouse C2C12 cells was greatly enhanced by the TGF-beta type I receptor kinase inhibitor SB431542. Endogenous TGF-beta was found to be highly active, and induced expression of Smad6 during the maturation phase of osteoblastic differentiation induced by BMP-4. SB431542 suppressed endogenous TGF-beta signaling and repressed the expression of Smad6 during this period, possibly leading to acceleration of BMP signaling. Thus, TGF-beta inhibitors may be invaluable for the treatment of various bone diseases by accelerating BMP-induced osteogenesis.
3)BMPs induce the proliferation of mouse ESC-derived endothelial cells and human microvascular endothelial cells (HMECs), and inhibit apoptosis of these cells. The expression of transcripts for Id-1,VEGFR2, and Tie-2 was upregulated by BMP-4, and phosphorylation of VEGFR-2 and Tie-2 was also induced by BMP-4. These findings suggest that BMP signaling activates the endothelium via activation of VEGF-A/VEGFR2 and Angiopoetin-Tie-2 signaling pathways.
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