| Project/Area Number |
21K20912
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0902:General internal medicine and related fields
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| Research Institution | Juntendo University |
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Principal Investigator |
Taiki Ando 順天堂大学, 医学部, 助手 (10912644)
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| Project Period (FY) |
2021-08-30 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | インフラマソーム / 肝臓線維化 / NLRP1 |
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| Outline of Research at the Start |
申請者の研究グループは、肝硬変を伴う希少疾患患者からNLRP1遺伝子の点変異（NLRP1-P1214L）を見出し、この変異がインフラマソームを活性化させて自己炎症性疾患を誘導すること、さらに、肝細胞におけるNLRP1インフラマソームの活性化が肝硬変につながる可能性を示した。しかし、その病態機序は十分に解明されていない。そこで、本研究は、NLRP1-P1214Lによる肝細胞のインフラマソーム活性化亢進が肝臓繊維化・肝硬変を引き起こす機序の解明を目指す。
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| Outline of Final Research Achievements |
We attempted to elucidate the mechanisms by which the NLRP1 point mutation, identified in a rare disease patient, caused liver cirrhosis. We demonstrated that NLRP1 inflammasome is constitutively activated in liver cell lines derived from this patient; however, we were not able to clarify the causal relationship between the NLRP1 inflammasome activation in hepatocytes and liver cirrhosis. We then generated the mice expressing this NLRP1 mutation specifically in hepatocytes. However, these mice neither exhibited NLRP1 inflammasome activation in hepatocytes nor liver abnormalities such as liver fibrosis. Accordingly, it was possible to speculate that in this patient, any infection and/or drug administration had triggered NLRP1 inflammasome activation, induced by this mutation, in hepatocytes. Further examination will be required to understand the relevant mechanisms.
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| Academic Significance and Societal Importance of the Research Achievements |
我々が同定した新規のNLRP1変異に関する本研究成果はNLRP1変異による自己炎症性疾患という概念の確立に寄与した。このように、本研究成果は学術的意義が高いと考えられる。また、インフラマソームを活性化させる機序の解明は特定の自己炎症性疾患の治療薬開発につながる可能性があり、本研究成果の社会的意義も高いと考えられる。
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