Regulation of biological defense responses via linear ubiquitin chains and its contribution to disease onset
Project/Area Number |
18K06967
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 49010:Pathological biochemistry-related
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Research Institution | Osaka City University |
Principal Investigator |
Oikawa Daisuke 大阪市立大学, 大学院医学研究科, 准教授 (20455330)
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Co-Investigator(Kenkyū-buntansha) |
徳永 文稔 大阪市立大学, 大学院医学研究科, 教授 (00212069)
|
Project Period (FY) |
2018-04-01 – 2021-03-31
|
Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
|
Keywords | 直鎖状ユビキチン鎖 / 炎症性疾患 / T細胞受容体 / NDP52 / NF-kB / 細胞死 |
Outline of Final Research Achievements |
Recently, linear ubiquitin chains produced by LUBAC have been attracting attention as a new regulator of defense responses, including NF-kB. In this study, the applicant identified a specific inhibitor of LUBAC, clarified the details of its molecular basis, and showed that it inhibits the growth of a specific type of B-cell lymphoma and the pathogenesis of psoriasis. We have also demonstrated that linear ubiquitin chains contribute to NF-kB activation by TCR stimulation in T cells, that NDP52 regulates NF-kB activity and TNF-a-induced apoptosis in a ubiquitin-binding capacity-dependent manner, and that NDP52 cooperates with linear ubiquitin chains in the regulation of Salmonella degradation (xenophagy).
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Academic Significance and Societal Importance of the Research Achievements |
細胞内で直鎖状ユビキチン鎖を産生する唯一のユビキチンリガーゼであるLUBACの機能破綻は、様々な疾患の発症と密接に関連する事が数多く報告されている。特に、ABC-DLBCL(活性化B細胞様びまん性大細胞型B細胞リンパ腫)は薬の効きにくい悪性リンパ腫であることが知られ、また、乾癬に対しても未だ有効な治療法は確立されておらず、現在、新たな視点に基づいた創薬ターゲットの創出が急務とされている。本研究において申請者らが同定した新規LUBAC阻害剤(HOIPIN)は、B細胞リンパ腫や乾癬の病態を抑制する事から、今後、これら疾患に対する新たな治療薬シーズとしての医療応用を期待したい。
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Report
(4 results)
Research Products
(45 results)
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[Journal Article] Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses.2020
Author(s)
Oikawa D, Sato Y, Ohtake F, Komakura K, Hanada K, Sugawara K, Terawaki S, Mizukami Y, Phuong HT, Iio K, Obika S, Fukushi M, Irie T, Tsuruta D, Sakamoto S, Tanaka K, Saeki Y, Fukai S, Tokunaga F.
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Journal Title
Communications Biology
Volume: -
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