| Project/Area Number |
16500335
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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 |
Rehabilitation science/Welfare engineering
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
MORITA Sadao TOKYO MEDICAL AND DENTAL UNIVERSITY, FACULTY OF MEDICINE, ASSOCIATE PROFESSOR, 医学部附属病院, 助教授 (20202426)
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| Co-Investigator(Kenkyū-buntansha) |
KUMEI Yasuhiro TOKYO MEDICAL AND DENTAL UNIVERSITY, GRADUATE SCHOOL, ASSISTANT PROFESSOR, 大学院医歯学総合研究科, 講師 (30161714)
SHIMOKAWA Hitoyata TOKYO MEDICAL AND DENTAL UNIVERSITY, GRADUATE SCHOOL, ASSOCIATE PROFESSOR, 大学院医歯学総合研究科, 助教授 (80014257)
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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 |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | bone atrophy / weightlessness / disuse syndrome / gene / signal transduction / stress response |
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| Research Abstract |
Long-term hospitalization induces disuse bone atrophy and bone fracture. Recently we reported that mechanical unloading attenuated RANKL in cultured osteoblasts. Our previous studies indicated that the IGF-I receptor docking protein, insulin receptor substrate-1 (IRS-1), was completely suppressed by weightlessness. IGF-I is one of the most important growth factor for bone. Mechanical unloading inhibited the IGF-I signaling. The IGF-I signals are transmitted via IRS-1, then to the small GTP-binding protein Ras via enhancing SOS, a Ras-activating protein. In the present study using osteoblast cultures, we examined first 1) the RANKL expression under mechanical loading, then 2) Ras activation, the upstream events leading to RANKL, and finally 3) the effects of small interfering RNA silencing of Ras (H-Ras) on the mechanoinduction of RANKL. We found that mechanical loading by 3OG-centrifugation increased mRNA expression of H-Ras and RANKL by 2-fold against 1G non-centrifugation control. We designed the Ras-specific silencing double strand RNAs, one of which effectively suppressed Ras. This Ras-siRNA was transfected into mouse osteoblasts, which showed no response to mechanical stimulation by 30G-centrifugation. These results indicate the specific role of H-Ras in mechano-induction of RANKL in osteoblasts. This study showed the involvement of Ras and RANKL in signal transduction by mechanical loading and unloading, and suggested the potential of clinical application in future.
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