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Elucidation of the entropy of tissue damage in digestive organs and development of new therapeutic approaches

Planned Research

Project AreaIntegrated elucidation of inflammatory tissue-resilience and tissue damage-entropy;Creation of innovative science for resolution of inflammation
Project/Area Number 21H05123
Research Category

Grant-in-Aid for Transformative Research Areas (B)

Allocation TypeSingle-year Grants
Review Section Transformative Research Areas, Section (III)
Research InstitutionKeio University

Principal Investigator

MIKAMI YOHEI  慶應義塾大学, 医学部(信濃町), 准教授 (80528662)

Project Period (FY) 2021-08-23 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥40,950,000 (Direct Cost: ¥31,500,000、Indirect Cost: ¥9,450,000)
Fiscal Year 2023: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2022: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2021: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Keywords炎症収束 / 炎症性腸疾患 / 肝炎 / 潰瘍性大腸炎 / クローン病 / 線維芽細胞 / 炎症収束学 / 線維化 / 神経免疫 / 1細胞遺伝子発現解析 / 神経 / シングルセル解析 / 組織障害エントロピー / 肝硬変
Outline of Research at the Start

近年、分子標的薬をはじめとする免疫統御療法の進歩に伴い、消化器系臓器の免疫難病における炎症制御成績は飛躍的に向上した。しかし、炎症が収束する過程で蓄積する不可逆的な組織障害に関しては、その病態に関与する責任細胞や背景の病態生理を含めて不明な点が多い。消化器系臓器における炎症・再生・線維化のプロセスにおいて、炎症収束に関わる責任細胞を特定するとともに、不可逆的な組織障害の蓄積の予防、治療に直結する病態メカニズムを解明する。

Outline of Final Research Achievements

In this study, we successfully established an intestinal fibrosis model induced by intestinal epithelial detachment to address the lack of model animals in the research of intestinal tissue remodeling or increase in entropy. Using the newly established intestinal fibrosis model animals and human samples, we conducted unbiased analyses of bulk RNA-seq and scRNA-seq data of stromal cells in the intestine, revealing the functional diversity of intestinal resident stromal cells. Furthermore, through integrative multi-omics analysis incorporating transcriptomic and epigenomic analyses such as ATAC-seq, we identified a novel fibroblast population that specifically arises during intestinal fibrosis.

Academic Significance and Societal Importance of the Research Achievements

炎症性腸疾患を含む広義の自己免疫性疾患の治療法として、分子標的療法は炎症制御に関しては革新的な治療革命をもたらしたものの、炎症収束後の組織レジリエンスには効果が乏しく、未だ炎症性腸疾患の根治療法は得られていない。本研究では、Omics解析を用いて、腸管組織障害に関与する新規のストローマ細胞集団を同定し、その分化経路の一端を明らかとするとともに、新規のストローマ細胞を標的とした革新的抗線維化治療に繋がる基盤的検討を示すことに成功した。ヒト検体およびモデル動物間の相同性相違性を解析することにより、種差を超えた普遍的な腸管組織エントロピー増大機構の一端を明らかとした。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (20 results)

All 2023 2022 2021 Other

All Int'l Joint Research (2 results) Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 5 results) Presentation (12 results) (of which Int'l Joint Research: 3 results,  Invited: 7 results) Remarks (1 results)

  • [Int'l Joint Research] 国立衛生研究所(米国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Sapienza University of Rome(イタリア)

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Divergent roles for STAT4 in shaping differentiation of cytotoxic ILC1 and NK cells during gut inflammation2023

    • Author(s)
      Scarno G, Mazej J, Laffranchi M, Di Censo C, Mattiola I, Candelotti AM, Pietropaolo G, Stabile H, Fionda C, Peruzzi G, Brooks SR, Tsai WL, Mikami Y, Bernardini G, Gismondi A, et al
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 120(40) Issue: 40

    • DOI

      10.1073/pnas.2306761120

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Myeloid TLR4 signaling promotes post-injury withdrawal resolution of murine liver fibrosis2023

    • Author(s)
      Takimoto Yoichi、Chu Po-sung、Nakamoto Nobuhiro、Hagihara Yuya、Mikami Yohei、Miyamoto Kentaro、Morikawa Rei、Teratani Toshiaki、Taniki Nobuhito、Fujimori Sota、Suzuki Takahiro、Koda Yuzo、Ishihara Rino、Ichikawa Masataka、Honda Akira、Kanai Takanori
    • Journal Title

      iScience

      Volume: 26 Issue: 3 Pages: 106220-106220

    • DOI

      10.1016/j.isci.2023.106220

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Heterogeneity of ILC2s in the Intestine; Homeostasis and Pathology2022

    • Author(s)
      Sunaga Shogo、Tsunoda Junya、Teratani Toshiaki、Mikami Yohei、Kanai Takanori
    • Journal Title

      Frontiers in Immunology

      Volume: 13

    • DOI

      10.3389/fimmu.2022.867351

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Enrichment of type I interferon signaling in colonic group 2 innate lymphoid cells in experimental colitis2022

    • Author(s)
      Irie Emi、Ishihara Rino、Mizushima Ichiro、Hatai Shunya、Hagihara Yuya、Takada Yoshiaki、Tsunoda Junya、Iwata Kentaro、Matsubara Yuta、Yoshimatsu Yusuke、Kiyohara Hiroki、Taniki Nobuhito、Sujino Tomohisa、Takabayashi Kaoru、Hosoe Naoki、Ogata Haruhiko、Teratani Toshiaki、Nakamoto Nobuhiro、Mikami Yohei、Kanai Takanori
    • Journal Title

      Frontiers in Immunology

      Volume: 13 Pages: 01-10

    • DOI

      10.3389/fimmu.2022.982827

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Organ and brain crosstalk: The liver-brain axis in gastrointestinal, liver, and pancreatic diseases2022

    • Author(s)
      Matsubara Yuta、Kiyohara Hiroki、Teratani Toshiaki、Mikami Yohei、Kanai Takanori
    • Journal Title

      Neuropharmacology

      Volume: 205 Pages: 108915-108915

    • DOI

      10.1016/j.neuropharm.2021.108915

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 疾患層別化、治療応用につながる免疫疾患の病態理解 1細胞遺伝子発現解析を用いた消化管線維芽細胞の多様性の理解2023

    • Author(s)
      三上 洋平, 高田 祐明, 萩原 裕也, 角田 潤也, 水島 一郎, 入江 江美, 石原 利乃, 佐藤 俊朗, 金井 隆典
    • Organizer
      日本臨床免疫学会総会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Enrichement of type I interferon signalling in the colonic ILC2 under inflammatory condition2023

    • Author(s)
      Yohei Mikami, Emi Irie, Rino Ishihara, Ichiro Mizushima, Takanori Kanai
    • Organizer
      IMMUNOLOGY2023™ AAI Annual Meeting
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 3.Assessment of mucosal inflammation for Crohn’s disease: safety and potential of intraoperative complete enteroscopy (ICE)2023

    • Author(s)
      Yohei MIKAMI, Koji OKABAYASHI, Takanori KANAI
    • Organizer
      第105回日本消化器内視鏡学会総会・国際セッション
    • Related Report
      2023 Annual Research Report
  • [Presentation] 1細胞遺伝子発現解析を用いた消化管の機能解析2023

    • Author(s)
      三上洋平,高田祐明,岩田賢太郎,入江江美,角田潤哉,水島一郎,萩原裕也,石原利乃,金井隆典.
    • Organizer
      日本消化器免疫学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] IBDのTreat to Targetの実際-治療選択のポイント 潰瘍性大腸炎に対する抗TNF-α抗体製剤セカンドラインの有効性に関する検討2023

    • Author(s)
      清原 裕貴, 三上 洋平, 金井 隆典
    • Organizer
      JDDW 2023 (Japan Digestive Disease Week 2023)
    • Related Report
      2023 Annual Research Report
  • [Presentation] 炎症収束学・その先へ: 慢性炎症と炎症性組織修復レジリエンスの統合的理解 多様性から迫る腸管恒常性維持機構と炎症性腸疾患病態の理解2023

    • Author(s)
      三上 洋平, 佐藤 俊朗, 金井 隆典
    • Organizer
      96回日本生化学会大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 腸管FOXP3+制御性T細胞の維持を介した大腸の免疫学的恒常性における非対称的迷走神経制御機構2023

    • Author(s)
      三上洋平
    • Organizer
      日本生理学会第100回記念大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Single cell analysis to better understand the pathogenesis of IBD2022

    • Author(s)
      三上洋平
    • Organizer
      The 1st International Symposium of Clinical Immunology
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 消化管粘膜の多様な細胞が織りなす消化器免疫学2022

    • Author(s)
      三上洋平
    • Organizer
      日本臨床免疫学会 免疫疾患横断セミナーシリーズ第3回 Human Immunology Priming Seminar ~様々な領域の分子標的療法から臨床免疫を理解しよう~
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 腸炎病態における腸管Th細胞の新規制御機構2022

    • Author(s)
      三上洋平, 寺谷俊昭, 金井隆典
    • Organizer
      第46回日本リンパ学会総会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 炎症性腸疾患における 免疫学的病態と臓器連関2022

    • Author(s)
      三上 洋平
    • Organizer
      千葉大学リーディング研究育成プログラム 「希少・難治性疾患に対する革新的治療創生研究」 希少・難治性疾患に対する革新的治療創生研究シンポジウム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Single-cell sequencing finds cell type-specific immune dysregulation in IBD2021

    • Author(s)
      Yohei Mikami
    • Organizer
      The 9th annual meeting of AOCC (AOCC 2021)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Remarks] Resolution of Inflammation

    • URL

      https://www.ensho-shusoku.jp/en/publication

    • Related Report
      2023 Annual Research Report

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Published: 2021-10-22   Modified: 2025-01-30  

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