| 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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