Elucidation of the molecular mechanism underlying the regulation of fibrosis-inducing-pathogenic CD4+ T cells
| Project/Area Number |
20H03685
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 53030:Respiratory medicine-related
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| Research Institution | Chiba University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2021: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
Fiscal Year 2020: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
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| Keywords | 病原性CD4+ T細胞 / single cell RNA-Seq / ATAC-Seq / 慢性炎症 / 線維化誘導-病原性CD4+ T細胞 / 肺の線維化 |
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| Outline of Research at the Start |
本申請研究では、慢性炎症による肺の病的リモデリング（線維化）を誘導する分子機構を明らかにすることを目的とする。具体的には、1. 肺の組織線維化に深く関与する線維化誘導-病原性CD4+ T細胞の分化経路の解析から、病原性機能の獲得や維持、組織常在性を司る転写因子を同定する。2. 慢性炎症時に肺の組織中に誘導される異所性リンパ組織の一種であるiBALTに着目し、微小環境（場）の１細胞レベルの網羅的解析から組織常在性を制御する環境側の因子の同定を目指す。3. ヒト（患者）の組織及び細胞で、最先端解析技術を用いて検証を行う。
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| Outline of Final Research Achievements |
We identified a group of genes that cause quantitative changes in fibrosis-induced-pathogenic CD4+ T cells. We have generated a gene-deficient mouse and a reporter mouse for one of these genes. We found; (1) CD4+ T cells from the gene-deficient mouse were markedly reduced in the lungs. (2) CD4+ T cells expressing the gene were frequently infiltrated in the nasal polyps of human eosinophilic sinusitis patients. The results of this study not only revealed a new function of pathogenic helper T cells in pathogenesis, but also identified a new molecular mechanism for their regulation. Based on the results of this study, we will continue our research to elucidate new regulatory mechanisms of CD4+ T cells that are deeply involved in the pathogenesis of chronic inflammatory diseases and to form the technological basis for the development of novel therapies for intractable allergic airway diseases for which there is no curative treatment.
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| Academic Significance and Societal Importance of the Research Achievements |
今回の研究結果は、病原性ヘルパーT細胞の病態形成における新たな機能を明らかにしただけでなく、その制御に関わる新たな分子機構を同定した。今後、本研究成果をもとに、慢性炎症疾患病態形成に深く関与するCD4+ T細胞の新たな制御機構が明らかになり、根治的治療法のない難治性アレルギー性気道疾患の新規治療法開発の技術基盤を形成すべく研究を続ける。
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Report
(4 results)
Research Products
(63 results)
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[Journal Article] Nematode ascarosides attenuate mammalian type 2 inflammatory responses2022
Author(s)
Shinoda Kenta、Choe Andrea、Hirahara Kiyoshi、Kiuchi Masahiro、Kokubo Kota、Ichikawa Tomomi、Hoki Jason S.、Suzuki Akane S.、Bose Neelanjan、Appleton Judith A.、Aroian Raffi V.、Schroeder Frank C.、Sternberg Paul W.、Nakayama Toshinori
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Journal Title
Proceedings of the National Academy of Sciences
Volume: 119(9)
Issue: 9
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Orally desensitized mast cells form a regulatory network with Treg cells for the control of food allergy.2021
Author(s)
Takasato Y, Kurashima Y, Kiuchi M, Hirahara K, Murasaki S, Arai F, Izawa K, Kaitani A, Shimada k, Saito Y, Toyoshima S, Nakamura M, Fujisawa K, Okayama Y, Kunisawa J, Kubo M, Takemura N, Uematsu S, Akira S, Kitaura J, Takahashi T, Nakayama T, Kiyono H
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Journal Title
Mucosal Immunol
Volume: 14
Issue: 3
Pages: 640-651
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Rapid remodeling of poised chromatin landscapes and transcription factor repurposing facilitate gene induction in natural killer cells.2020
Author(s)
Sciume G, Mikami Y, Jankovic D, Nagashima H, Villarino AV, Morrison T, Signorella S, Yao C, Sun HW, Brooks SR, Fang D, Sartorelli V, Nakayamada S, Hirahara K, Zitti B, Davis FP, Kanno Y, O’Shea JJ, Shih HY
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Journal Title
Immunity
Volume: 53(4)
Issue: 4
Pages: 745-758
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] The effect of tissue hypoxia on the immune system in chronic inflammatory lung diseases Presenter2023
Author(s)
Sasaki, A., Kiuchi, M., Yagyu, H., Tsuji, K., Suzuki, T., Nakayama, T., and Hirahara, K.
Organizer
International Symposium for Future Mucosal Vaccines: Safeguards and Innovations against Infectious Diseases
Related Report
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[Presentation] Unsaturated fatty acids promote pathogenic type 2 adaptive immunity via PPARg-ST2 axis2023
Author(s)
Yagyu, H., Kiuchi, M., Kokubo, K., Sasaki, A., Onodera, A., Iwamura, C., Kaneko, T., Nakayama T., and Hirahara, K.
Organizer
International Symposium for Future Mucosal Vaccines: Safeguards and Innovations against Infectious Diseases
Related Report
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[Presentation] Role of amphiregulin-producing pathogenic T helper 2 cells in the fibrotic responses in eosinophilic esophagitis2023
Author(s)
Kaneko, T., Iwamura, C., Kiuchi, M., Kurosugi, A., Hirahara, K., and Nakayama, T.
Organizer
International Symposium for Future Mucosal Vaccines: Safeguards and Innovations against Infectious Diseases
Related Report
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[Presentation] Elevated Myl9 reflects the Myl9-containing microthrombi in SARS-CoV-2-induced lung exudative vasculitis and predicts COVID-19 severity2022
Author(s)
Iwamura, C., Hirahara, K., Nemoto, M., Tsuji, K., Onoue, M., Kurosugi, A., Sasaki, A., and Nakayama, T.
Organizer
第51回日本免疫学会学術集会
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