| Project/Area Number |
17390411
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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 |
KARITA Tatsuro The University of Tokyo, Faculty of Medicine, Lecturer (80359611)
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| Co-Investigator(Kenkyū-buntansha) |
OGATA Naoshi The University of Tokyo, Faculty of Medicine, Visiting Faculty Member (10361495)
HARA Yukinori The University of Tokyo, Faculty of Medicine, Research Associate (30396741)
川口 浩 東京大学, 医学部附属病院, 助教授 (40282660)
村上 元昭 東京大学, 医学部附属病院, 医員 (50396751)
中村 耕三 東京大学, 医学部附属病院, 教授 (60126133)
石山 典幸 東京大学, 医学部附属病院, 医員 (60376481)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,590,000 (Direct Cost: ¥15,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2007: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2006: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 2005: ¥6,000,000 (Direct Cost: ¥6,000,000)
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| Keywords | klotho / insulin / ageing / bone / 軟骨 / IGF-I / 骨粗鬆症 / 変形性関節症 |
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| Research Abstract |
Klotho and insulin/IGF-I has been reported to be the principal signals in ageing and the related disorders. The present project sought to examine the interaction of the two signals in ageing and a representative age-related disorder osteoporosis.
We previously reported that a defect in Klotho gene expression leads to a syndrome that may resemble premature aging. In the present project, we found that overexpression of Klotho can extend life span, and we suggest that Klotho functions as an aging suppressor gene in mammals. We further found that the extracellular domain of Klotho protein circulates in the blood and binds to a putative cell-surface receptor. Klotho has marked effects on insulin physiology, apparently because it suppresses tyrosine phosphorylation of insulin and IGF1 receptors, which results in reduced activity of IRS proteins and their association with P13-kinase, thereby inhibiting insulin and IGF1 signaling. Extended life span upon negative regulation of insulin and IGF1 signaling is an evolutionarily conserved mechanism to suppress aging. Klotho appears to be a peptide hormone to modulate such signaling and thereby mediate insulin metabolism and aging.
Contrarily our in vivo and in vitro examinations failed to find the interaction between the two signals with age-related bone metabolism. These indicate that the two signals interact each other during systemic ageing process, although they have distinct mechanism of regulation of bone remodeling.
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