| Project/Area Number |
18390409
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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 |
Orthopaedic surgery
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| Research Institution | The University of Tokyo |
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Principal Investigator |
INOUE Jun-ichiro The University of Tokyo, Institute of Medical Science, Professor (70176428)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
|
| Budget Amount *help |
¥17,620,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥2,220,000)
Fiscal Year 2007: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
Fiscal Year 2006: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Keywords | signal transduction / development & differentiation / bone metabolism / drug discovery / bone metastasis / rheumatoid arthritis / osteoporosis |
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| Research Abstract |
TRAF6 is essential for osteoclastogenesis and plays a crucial role in both RANK- and CD40-mediated activation of IKK and MAPKs in osteoclast progenitor cells. Despite the requirement for IKK and MAPKs activation in osteoclastogenesis, RANK, but not CD40, can promote osteoclastogenesis because only RANK can induce long-term activation of the co-stimulatory signals mediated by immunoglobulin-like receptors/ITAM-containing adaptors complexes, which are required for induction of NFATcl, a master gene in osteoclastogenesis. Our previous data suggested that RANK, but not CD40, harbors a unique domain that functions in concert with the TRAF6-binding site to activate the co-stimulatory signals in a sustainable way and promote osteoclastogenesis. We identify such a functional protein domain, HCR, that is highly conserved in RANKs from various vertebrates and is essential for long-term activation of co-stimulatory signals. Addition of the HCR to the cytoplasmic tail of CD40 renders CD40 capable of inducing sustained activation of co-stimulatory signals and subsequent activation of NFATcl. Furthermore, the HCR dramatically enhances internalization of HCR-harboring receptors upon stimulation. These results suggest that the HCR can continuously link the RANK-TRAF6 axis to sustained co-stimulatory signaling pathways through control of the membrane trafficking of receptors and that the HCR may be a novel therapeutic target for pathological bone resorption.
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