2021 Fiscal Year Final Research Report
Chemical identification of activation factors in mitochondrial DAMPs and their regulatory mechanisms in innate immunity
| Project/Area Number |
19K05853
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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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| Review Section |
Basic Section 38040:Bioorganic chemistry-related
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| Research Institution | Nagahama Institute of Bio-Science and Technology |
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Principal Investigator |
Mukai Hidehito 長浜バイオ大学, バイオサイエンス学部, 教授 (20251027)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | クリプタイド / 生体機能物質 / 自然免疫機構 / 好中球 / 肝傷害モデル / エンドトキシン / 炎症 / 活性発現の分子機構 |
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| Outline of Final Research Achievements |
Mitocryptides (MCTs) including mitocryptide-1 (MCT-1), mitocryptide-2 (MCT-2) and mitocryptide-3 (MCT-3) are a family of novel neutrophil-activating peptides derived from various mitochondrial proteins. Here we suggested the novel mechanisms that initiate innate immune responses. Indeed, the receptor molecule for MCT-2 was shifted from formyl-peptide receptor-2 to formyl-peptide receptor-1 depending on the truncation of MCT-2 from C-terminus. It was also suggested that MCT-3 as well as MCT-1 directly activated Gαi2 protein that was located at the surface of neutrophilic plasma membrane. We also demonstrated that intravenous pre-injection of neutralizing antibodies against MCT-2 suppressed neutrophil infiltration and promoted recovery of the tissue in the mouse hepatic injury model caused by lipopolysaccharide (LPS), indicating that MCT-2 involves not only in the tissue damage mechanisms induced by LPS but also in recovery from the damage.
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| Free Research Field |
ペプチド科学・ペプチド創薬
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、我々が世界に先駆けて発見した、ミトコンドリアタンパク質由来の一群の新規好中球活性化ペプチド、「マイトクリプタイド」（MCTs）の生体における役割を解明するため、まずMCTsとmtDAMPsとの関連を検討した。その結果、実際にmtDMPs中にMCT-2およびMCT-3が存在していることが明らかになった。また、LPSにより実験的に誘導した肝傷害モデルにおいて、MCT-2がその増悪および再生、両者に関わる可能性を世界で初めて示すことに成功した。この研究成果は、多臓器不全や虚血傷害といった未だ有効な治療法が確立されていない炎症性疾病の治療に道を開く画期的成果であると考えられる。
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