| 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 |
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| Section | 一般 |
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| Review Section |
Basic Section 49010:Pathological biochemistry-related
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| Research Institution | Osaka City University |
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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)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| 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)
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| 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 |
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| 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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