Global identification of the substrates of protein crosslinking enzyme and the development of preventive drug in tissue fibrosis
| Project/Area Number |
16K09353
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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 |
Gastroenterology
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| Research Institution | Nagoya University |
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Principal Investigator |
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| Research Collaborator |
HITOMI kiyotaka
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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 |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | 架橋酵素 / 肝線維化 / 肝硬変 / サイトケラチン / 架橋 / 基質探索 / 質量分析 / 線維化 / タンパク質架橋化酵素 / トランスグルタミナーゼ / 抗線維化薬 / 肝臓 |
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| Outline of Final Research Achievements |
The transglutaminase (TG) family comprises eight isozymes that catalyze the crosslinking reaction between glutamine and lysine residues and contribute to the fibrotic diseases in several tissues. Despite the evidence implicating TG2 as a key enzyme in fibrosis, the causative role and involvement of the other isozymes have not yet been fully elucidated. Therefore, here we clarified the distributions and activities of TG isozymes, and identified the isozyme-specific substrates for both TG1 and TG2 using each substrate peptide. The possible substrates for each TG were successfully identified and these included keratin 18, a biomarker for hepatic injury, which was accumulated in the fibrotic liver. Our findings suggest that each TG was independently activated in a different tissue area during fibrotic induction, and played a potential role in the functional modification of keratin 18, which are relevant to liver fibrosis progression.
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| Academic Significance and Societal Importance of the Research Achievements |
多くの疾患は単に発現したタンパク質量の変化により引き起こされるものではなく、多くの翻訳後修飾反応を含む様々な制御因子の破綻によって誘導される。本研究では、タンパク質間にイソペプチド結合を形成することによりタンパク質の機能を変化させる翻訳後修飾反応の一つに着目し、この反応が肝硬変のような臓器が硬化する慢性疾患で見られることを明らかにした。またこの修飾反応の阻害は上記の慢性疾患を緩和することも明らかにした。これらの結果は今後の同疾患の新たな予防・治療法の開発に繋がることが期待される。
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Report
(4 results)
Research Products
(37 results)
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[Journal Article] Prevention of hepatocellular carcinoma by targeting MYCN-positive liver cancer stem cells with acyclic retinoid2018
Author(s)
Qin XY, Suzuki H, Honda M, Okada H, Kaneko S, Inoue I, Ebisui E, Hashimoto K, Carninci P, Kanki K, Tatsukawa H, Ishibashi N, Masaki T, Matsuura T, Kagechika H, Toriguchi K, Hatano E, Shirakami Y, Shiota G, Shimizu M, Moriwaki H, Kojima S
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Journal Title
Proc Natl Acad Sci U S A
Volume: 115
Issue: 19
Pages: 4969-4974
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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