The development of low-molecular compound for the new method to stimultate bone formation by targetting protein-protein interaction
| Project/Area Number |
16K11456
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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 |
Morphological basic dentistry
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| Research Institution | Kyushu Dental College |
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Principal Investigator |
Min Zhang 九州歯科大学, 歯学部, 助教 (00326472)
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| Co-Investigator(Kenkyū-buntansha) |
松原 琢磨 九州歯科大学, 歯学部, 助教 (00423137)
松尾 拡 九州歯科大学, 歯学部, 教授 (70238971)
古株 彰一郎 九州歯科大学, 歯学部, 教授 (30448899)
自見 英治郎 九州大学, 歯学研究院, 教授 (40276598)
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| Research Collaborator |
URATA Mariko
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | BMP / 骨形成 / Smad / p65 / 骨再生 / ペプチド / NF-κB / 創薬 |
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| Outline of Final Research Achievements |
Bone morphogenetic protein (BMP) potentiates bone formation through the Smad signaling pathway. The transcription factor nuclear factor κB (NF-κB) suppresses BMP-induced osteoblast differentiation. Recently, we identified that the transactivation (TA) 2 domain of p65, a main subunit of NF-κB, interacts with the mad homology (MH) 1 domain of Smad4 to inhibit BMP signaling. Therefore, we further attempted to identify the interacting regions of these two molecules at the amino acid level. We identified a region that we term the Smad4-binding domain (SBD). Cell-permeable SBD peptide blocked the association of p65 with Smad4 and enhanced BMP2-induced osteoblast differentiation and mineralization. Although SBD peptide did not affect BMP2-induced chondrogenesis during ectopic bone formation, the peptide enhanced BMP2-induced ectopic bone formation in subcortical bone. Thus, the SBD peptide is useful for enabling BMP2-induced bone regeneration without inhibiting NF-κB activity.
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| Academic Significance and Societal Importance of the Research Achievements |
以前から他の研究室や我々の報告からNF-κBの阻害はBMPの骨芽細胞分化や骨形成に有利であると考えられてきた。しかしながら、NF-κBのメインサブユニットであるp65欠損マウスは肝臓のアポトーシスによる胎生致死であることからNF-κBの阻害剤の長期投与は重篤な副作用を引き起こす可能性がある。このような背景から、今回見出したNF-κBのp65とSmad4の会合部位を特異的に阻害するSBDペプチドは、NF-κBの機能を完全に失うことなく、効率良くBMPによる骨形成、骨再生の促進効果を発揮できる画期的な薬剤となる可能性がある。
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Report
(4 results)
Research Products
(6 results)
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[Journal Article] Geranylgeraniol Induces PPARγ Expression and Enhances the Biological Effects of a PPARγ Agonist in Adipocyte Lineage Cells.2018
Author(s)
T Matsubara, N Takaura, M Urata, Y Muramatsu, M Tsuboi, K Yasuda, W Addison, M Zhang, K Matsuo, C Nakatomi, Y S Tada, T Kaneuji, A Nakamichi and S Kokabu:
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Journal Title
In vivo
Volume: 32
Issue: 6
Pages: 1339-1344
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Geranylgeraniol-induced Myogenic Differentiation of C2C12 Cells.2018
Author(s)
T Matsubara, M Urata, T Nakajima, M Fukuzaki, R Masuda, Y Yoshimoto, W Addison, K Morikawa, M Zhang, K Saeki, Y Takahashi, A Nakamichi and S Kokabu:
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Journal Title
In vivo
Volume: 32
Issue: 6
Pages: 1427-1432
DOI
Related Report
Peer Reviewed
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[Journal Article] A peptide that blocks the interaction of NF-κB p65 subunit with Smad4 enhances BMP2-indeuce osteogenesis.2018
Author(s)
Urata M, Kokabu S, Matsubara T, Sugiyama G, Nakatomi C, Takeuchi H, Hirata TS, Aoki K, Tamura Y, Moriyama Y, Ayukawa Y, Matsuda M, Zhang M, Koyano K, Kitamura C, Jimi E.
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Journal Title
J Cell Physiol.
Volume: 1
Issue: 9
Pages: 1-11
DOI
Related Report
Peer Reviewed / Open Access
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