Analysis of the mechanism of autoinflammatory disorder induction due to proteasome dysfunction
| Project/Area Number |
16K09922
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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 |
Collagenous pathology/Allergology
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| Research Institution | The University of Tokushima |
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Principal Investigator |
SASAKI Yuki 徳島大学, 大学院医歯薬学研究部(医学域), 助教 (50454757)
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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 |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 自己炎症 / プロテアソーム / 免疫プロテアソーム / 炎症学 / 免疫学 |
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| Outline of Final Research Achievements |
The mutation in PSMB8 causes autoinflammation and lipodystrophy due to low activity of immunoproteasomes in human. The molecular basis of these symptoms, however, remains undetermined. We established a mouse that harbors a mutation in Psmb8 (Psmb8-KI mouse) in order to analyze the molecular mechanisms of various symptoms in patients with a mutation in PSMB8.
Psmb8-KI mouse exhibits increased sensitivity for imiquimod-induced dermatitis. The dermatitis in Pmsb8-KI and wild type mouse was suppressed by the inhibition of inflammatory cytokines but neither inhibition was effective to cancel the increased sensitivity in Psmb8-KI mouse. I found that the ear of IMQ-treated KI mice expressed higher X gene expression than wild type mice. The inhibitor of X-related pathway treatment suppressed the increased swelling of the ear observed in Psmb8-KI mice.
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| Academic Significance and Societal Importance of the Research Achievements |
PSMB8のミスセンス変異は、JASLと同様の臨床症状を呈する中條・西村症候群などでも見いだされ、近年これらの症候群はプロテアソーム関連自己炎症症候群 (PRAAS)と呼称されPSMB8以外のサブユニットの変異も報告されている。しかしPRAASの詳しい発症機構は解明されていない。ヒトと同じ変異を持つPsmb8-KIマウスを樹立し解析を行った結果、本研究では免疫プロテアソームの機能破綻がどのように炎症病態を誘導しているかについての分子機構の一端を明らかにした。今後PSMB8が様々な炎症病態にどのように機能しているかを解明することは慢性炎症性疾患に対する治療法の開発に大きく貢献すると期待できる。
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Report
(4 results)
Research Products
(1 results)
