| Project/Area Number |
21F21112
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| Research Category |
Grant-in-Aid for JSPS Fellows
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| Allocation Type | Single-year Grants |
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| Section | 外国 |
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| Review Section |
Basic Section 49070:Immunology-related
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| Research Institution | Osaka University |
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Principal Investigator |
竹田 潔 大阪大学, 大学院医学系研究科, 教授 (20309446)
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| Co-Investigator(Kenkyū-buntansha) |
LI BO 大阪大学, 医学(系)研究科(研究院), 外国人特別研究員
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| Project Period (FY) |
2021-04-28 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2022: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2021: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | intestine stromal cell / ubiquitination / intestine / stromal cell |
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| Outline of Research at the Start |
Several subsets of intestinal stromal cells were identified. However, it remains unclear whether intestinal stromal cells are implicated in the pathogenesis of IBD. Single nucleotide polymorphism of the OTU domain-containing protein 3 (Otud3) gene, which is highly expressed in intestinal stromal cells, is reported in ulcerative colitis. Therefore, we will analyze the function of Otud3 in the maintenance of intestinal homeostasis. This study will reveal a novel stromal cell-dependent mechanism for the pathogenesis of IBD.
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| Outline of Annual Research Achievements |
To assess the physiological function of OTUD3 in the intestine, we generated Otud3 deficient mice by using gene targeting. We observed that deficient mice exhibited more severe colitis during DSS administration.In murine colon, Otud3 mRNA was highly expressed in fibroblasts relative to epithelia cells and innate and adaptive immune cells. Otud3 deficiency in fibroblasts leads to aggravation of colitis.By performing scRNA-seq analysis using colonic fibroblasts, we found
OTUD3 modulates the STING-IFN signaling pathway in a special subset of colonic fibroblasts.By making use of antibiotics (ABX) treatment and germ free mice, we found OTUD3 modulates the microbial cGAMP-STING-IFN pathway in colonic fibroblasts.We generated a knock-in strain of OTUD3 UC risk variant mice, and confirmed this UC risk variant in OTUD3 is associated with dysregulation of STING activation in intestinal fibroblasts.
Now I am preparing to submit the paper to a major acdemic journal.Fibroblasts, the most abundant structural cells, exert homeostatic functions but also drive disease pathogenesis. Single-cell technologies have illuminated the shared characteristics of pathogenic fibroblasts in multiple diseases. However, the molecular mechanisms underlying the disease-associated fibroblast phenotypes remain largely unclear. Our findings provide a mechanistic basis for pathogenic fibroblast polarization and have important therapeutic implications
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| Research Progress Status |
令和4年度が最終年度であるため、記入しない。
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| Strategy for Future Research Activity |
令和4年度が最終年度であるため、記入しない。
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