2016 Fiscal Year Final Research Report
Elucidation of pathological molecular mechanism of Notch2-Hajdu Cheney Syndrome type mutation
| Project/Area Number |
26462829
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Functional basic dentistry
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| Research Institution | Tohoku University (2015-2016)
Fukuoka Dental College (2014) |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
自見 英治郎 九州歯科大学, 歯学部, 教授 (40276598)
岡本 富士雄 福岡歯科大学, 口腔歯学部, 講師 (60153938)
鍛治屋 浩 福岡歯科大学, 口腔歯学部, 講師 (80177378)
岡部 幸司 福岡歯科大学, 口腔歯学部, 教授 (80224046)
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| Co-Investigator(Renkei-kenkyūsha) |
Inuzuka Hiroyuki 東北大学歯学研究科, 歯学部, 准教授 (20335863)
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| Research Collaborator |
Wei Wenyi ハーバード大学, 医学部, 教授
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Keywords | Hajdu-Cheney症候群 / ユビキチン / プロテアソーム / FBW7 / Notch2 / 破骨細胞 / Osteolysis / 骨融解症 |
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| Outline of Final Research Achievements |
Hajdu-Cheney syndrome (HCS) is a rare autosomal disorder caused by heterozygous mutations in NOTCH2, clinically characterized by acroosteolysis, severe osteoporosis, short stature and polycystic kidneys. Recent studies have identified that aberrant NOTCH2 signaling and consequent osteoclast hyperactivity are closely associated with pathogenesis of the bone-related disorder, but exact molecular mechanisms remain largely elusive. We found that the sustained osteoclast activity is largely due to elevated protein abundance of C-terminus truncating mutant of NOTCH2 that escapes FBW7-mediated ubiquination and proteolysis events. Mice with osteoclast-specific Fbw7 ablation revealed osteoporotic phenotypes reminiscent of HCS owing to elevated Notch2 signaling. Importantly, administrations of Notch inhibitors in the Fbw7 conditional knockout mice alleviated progressive bone resorption. Our findings highlight the molecular basis for the pathogenesis of HCS.
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| Free Research Field |
骨代謝
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