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Investigation of mechanisms on autoinflammatory diseases caused by NLRP1 mutation

Research Project

Project/Area Number 21K20912
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0902:General internal medicine and related fields
Research InstitutionJuntendo University

Principal Investigator

Taiki Ando  順天堂大学, 医学部, 助手 (10912644)

Project Period (FY) 2021-08-30 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
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)
Keywordsインフラマソーム / 肝臓線維化 / NLRP1
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。

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.

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。

Report

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

    (21 results)

All 2023 2022 2021

All Journal Article (8 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 7 results,  Open Access: 4 results) Presentation (13 results) (of which Invited: 1 results)

  • [Journal Article] Polyarteritis nodosa diagnosed in a young male after COVID-19 vaccine: A case report2023

    • Author(s)
      Makiyama Ayako、Abe Yoshiyuki、Furusawa Hoshiko、Kogami Masahiro、Ando Taiki、Tada Kurisu、Onimaru Mitsuho、Ishizu Akihiro、Yamaji Ken、Tamura Naoto
    • Journal Title

      Modern Rheumatology Case Reports

      Volume: 8 Issue: 1 Pages: 125-132

    • DOI

      10.1093/mrcr/rxad037

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A case of cryopyrin-associated periodic syndrome due to somatic mosaic mutation complicated with recurrent circinate erythematous psoriasis2023

    • Author(s)
      Ando Taiki、Abe Yoshiyuki、Yamaji Ken、Nishikomori Ryuta、Tamura Naoto
    • Journal Title

      Modern Rheumatology Case Reports

      Volume: - Issue: 2 Pages: 368-372

    • DOI

      10.1093/mrcr/rxad067

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Avacopan is possibly associated with the improvement of ANCA-associated vasculitis activity without decreasing ANCA titres: a four-case series2023

    • Author(s)
      Abe Y, Minowa K, Kogami M, Ando T, Makiyama A, Yamaji K, Tamura N.
    • Journal Title

      Rheumatology (Oxford)

      Volume: - Issue: 11 Pages: e317-e318

    • DOI

      10.1093/rheumatology/kead191

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Performance of classification and diagnostic criteria for IgG4-related disease and comparison of patients with and without IgG4-related disease2023

    • Author(s)
      Kogami M, Abe Y, Ando T, Makiyama A, Yamaji K, Tamura N.
    • Journal Title

      Sci Rep.

      Volume: 13 Issue: 1 Pages: 2509-2509

    • DOI

      10.1038/s41598-023-29645-2

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Changes in anti-MDA5 antibody titres and serum cytokine levels before and after diagnosis of anti-MDA5 antibody-positive dermatomyositis2022

    • Author(s)
      Kogami M, Abe Y, Ando T, Makiyama A, Yamaji K, Tamura N.
    • Journal Title

      Rheumatology (Oxford).

      Volume: - Issue: 7 Pages: 2525-2533

    • DOI

      10.1093/rheumatology/keac627

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Systematic review and meta-analysis for 2023 clinical practice guidelines of the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis for the management of ANCA-associated vasculitis2022

    • Author(s)
      Watanabe Ryu、Oshima Megumi、Nishioka Norihiro、Sada Ken-Ei、Nagasaka Kenji、Akiyama Mitsuhiro、Ando Taiki、Higuchi Tomoaki、Inoue Yoshino、Kida Takashi、Mutoh Tomoyuki、Nakabayashi Akihiko、Onishi Akira、Sakai Ryota、Waki Daisuke、Yamada Yosuke、Yajima Nobuyuki、Tamura Naoto、Kaname Shinya、Harigai Masayoshi
    • Journal Title

      Modern Rheumatology

      Volume: - Issue: 5 Pages: 982-989

    • DOI

      10.1093/mr/roac114

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] 自己炎症性疾患における原因遺伝子解析2022

    • Author(s)
      安東泰希、前原明絵、田村直人、北浦次郎
    • Journal Title

      リウマチ科

      Volume: 68 Pages: 371-378

    • Related Report
      2022 Research-status Report
  • [Journal Article] A possible association between a novel NLRP1 mutation and an autoinflammatory disease involving liver cirrhosis2021

    • Author(s)
      Yasudo Hiroki、Ando Taiki、Maehara Akie、Ando Tomoaki、Izawa Kumi、Tanabe Atsushi、Kaitani Ayako、Nomura Shigeru、Seki Masafumi、Yoshida Kenichi、Oda Hirotsugu、Okamoto Yoko、Wang Hexing、Kamei Anna、Kojima Mayuki、Kimura Meiko、Uchida Koichiro、Nakano Nobuhiro、Kaneko Junichi、et al.
    • Journal Title

      Hepatology

      Volume: - Issue: 4 Pages: 2296-2299

    • DOI

      10.1002/hep.31818

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] SLE合併妊娠 当院におけるヒドロキシクロロキンのSLE合併妊娠に対する有効性の検討2023

    • Author(s)
      安東 泰希 , 安倍 能之 , 竹内 幹 , 小神 昌寛 , 牧山 彩子 , 多田 久里守 , 山路 健 , 田村 直人
    • Organizer
      第67回日本リウマチ学会総会・学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 希少疾患患者から同定されたNLRP1点変異(P1214L)は自己炎症性疾患を誘導する2023

    • Author(s)
      安東泰希、前原明絵、安戸裕貴、伊沢久未、安藤智暁、貝谷綾子、田村直人、北浦次郎
    • Organizer
      第6回日本免疫不全・自己炎症学会総会・学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] NLRP1変異による自己炎症性疾患の病態2023

    • Author(s)
      北浦次郎、安東泰希、前原明絵、安戸裕貴、山本里彩、伊沢久未、安藤智暁、貝谷綾子、田村直人
    • Organizer
      第6回日本免疫不全・自己炎症学会総会・学術集会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] 肝臓繊維化を伴う希少疾患患者から同定されたNLRP1点変異はインフラマソームを強く活性化する2022

    • Author(s)
      安東泰希、前原明絵、安戸裕貴、伊沢久未、安藤智暁、貝谷綾子、山路健、奥村康、小川誠司、田村直人、北浦次郎
    • Organizer
      第43回日本炎症・再生医学会
    • Related Report
      2022 Research-status Report
  • [Presentation] NLRP1-P1214L点変異はNLRP1とdipeptidyl peptidase 9(DPP9)の結合を阻害することによりNLRP1インフラマソームの活性化を亢進させる2022

    • Author(s)
      山本里彩、前原明絵、安東泰希、安戸裕貴、伊沢久未、安藤智暁、貝谷綾子、奥村康、小川誠司、田村直人、北浦次郎
    • Organizer
      第27回日本病態プロテアーゼ学会学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] A point mutation of NLRP1 (NLRP1-P1214L), identified in a patient with a rare disease, causes an auto-inflammatory disease through hyper-activation of inflammasome: molecular analysis of the pathophysiology2022

    • Author(s)
      Yamamoto Risa, Maehara Akie, Ando Taiki, Yasudo Hiroki, Izawa Kumi, Ando Tomoaki, Kaitani Ayako, Kitaura Jiro
    • Organizer
      第54回日本小児感染症学会総会・学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] ヒトNLRP1の点変異により誘導される自己炎症性疾患の病態解析2022

    • Author(s)
      山本里彩、安東泰希、安戸裕貴、安藤智暁、山路健、奥村康、田村直人、北浦次郎
    • Organizer
      第32回日本リウマチ学会関東支部学術集会
    • Related Report
      2022 Research-status Report
  • [Presentation] NLRP1点変異が肝臓線維化を主徴とする自己炎症性疾患を誘導した症例2021

    • Author(s)
      安東泰希、前原明絵、安戸裕貴、安藤智暁、伊沢久未、田辺篤、貝谷綾子、亀井杏菜、王合興、金子順一、山路健、奥村康、小川誠司、田村直人、北浦次郎
    • Organizer
      第49回日本臨床免疫学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 肝臓線維化を主徴とする稀少疾患患者から同定されたNLRP1変異の機能解析2021

    • Author(s)
      安東泰希、前原明絵、安藤智暁、伊沢久未、北浦次郎、田村直人
    • Organizer
      第118回日本内科学会
    • Related Report
      2021 Research-status Report
  • [Presentation] 肝臓線維化を主徴とする希少疾患患者から同定されたNLRP1変異の機能解析2021

    • Author(s)
      安東泰希、前原明絵、安戸裕貴、安藤智暁、伊沢久未、田辺篤、貝谷綾子、亀井杏菜、王合興、金子順一、山路健、奥村康、小川誠司、田村直人、北浦次郎
    • Organizer
      第58回日本消化器免疫学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] A point mutation within the function-to-find domain (FIIND) of human NLRP1 causes an autoinflammatory disease involving liver fibrosis and dyskeratosis.2021

    • Author(s)
      Akie Maehara, Taiki Ando, Kumi Izawa, Tomoaki Ando, Ayako Kaitani, Anna Kamei, Hexing Wang, Koji Tokushige, Nobuhiro Nakano, Naoto Tamura, Ko Okumura, Jiro Kitaura
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] ヒトNLRP1のFIINDにおける点変異(P1214L)は自己炎症性疾患を誘導する2021

    • Author(s)
      前原明絵、安東泰希、安戸裕貴、伊沢久未、安藤智暁、貝谷綾子、田村直人、北浦次郎
    • Organizer
      第5回日本免疫不全・自己炎症学会 総会・学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 肝硬変を伴う希少疾患患者から同定されたNLRP1点変異の機能解明2021

    • Author(s)
      前原明絵、安東泰希、安戸裕貴、伊沢久未、安藤智暁、貝谷綾子、奥村康、小川誠司、田村直人、北浦次郎
    • Organizer
      第30回東京免疫フォーラム
    • Related Report
      2021 Research-status Report

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

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