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New paradigm for innate immune regulatory mechanism and chronic inflammation mediated by ganglioside molecular species

Research Project

Project/Area Number 17K19569
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Research Field Pathology, Infection/Immunology, and related fields
Research InstitutionTohoku Medical and Pharmaceutical University

Principal Investigator

INOKUCHI Jin-ichi  東北医科薬科大学, 薬学部, 教授 (70131810)

Co-Investigator(Kenkyū-buntansha) 鈴木 明身  東北医科薬科大学, 薬学部, 客員教授 (70134533)
Project Period (FY) 2017-06-30 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
KeywordsGM3ガングリオシド / 慢性炎症 / TLR4 / グロボシド / 糖尿病性腎症 / 自然免疫 / ガングリオシド / GM3 / メタボリックシンドローム / ガングリオシドGM3
Outline of Final Research Achievements

The aim of this project is the elucidation of molecular mechanisms involved in the vicious cycle of chronic inflammation state induced by GM3 ganglioside-molecular species, and the examination of potential application of this evidence to the establishing of diagnosis and treatment for the vicious cycle.
90% of total gangliosides of human sera are GM3 molecular species. We have found a surprising evidence that very-long chain (VLCFA)-GM3 induce the secretion of inflammatory cytokines when monocytes or macrophages are stimulated by the TLR4 ligand, LPS or HMGB1, while long chain (LCFA)-GM3 suppress the secretion of inflammatory cytokines. Collectively, we propose a novel inflammation loop triggered by GM3 molecular species.

Academic Significance and Societal Importance of the Research Achievements

TLR4に作用する炎症促進性GM3分子種および炎症抑制性GM3分子種が存在し、メタボリックシンドロームの進行に沿って、発現バランスが炎症促進性へシフトすることを見出した。これらのGM3分子種の生理活性は、セラミド構造中のアシル鎖の鎖長や飽和度、水酸化修飾によって制御されており、炎症促進性GM3分子種は極長鎖飽和アシル鎖をもつ分子種であり、一方、炎症抑制性GM3分子種は、長鎖または不飽和アシル鎖をもつ分子種であった。これらの知見から、患者血清中のGM3分子種の定量解析による慢性炎症状態の診断・評価法の開発や、炎症抑制性GM3投与による新たな慢性炎症制御法の開発が期待できる。

Report

(3 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • Research Products

    (37 results)

All 2019 2018 2017 Other

All Int'l Joint Research (1 results) Journal Article (14 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 14 results,  Open Access: 3 results,  Acknowledgement Compliant: 1 results) Presentation (20 results) (of which Int'l Joint Research: 8 results,  Invited: 9 results) Book (1 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] University of Milano(Italy)

    • Related Report
      2017 Research-status Report
  • [Journal Article] Globo-series glycosphingolipids enhance Toll-like receptor 4-mediated inflammation and play a pathophysiological role in diabetic nephropathy.2019

    • Author(s)
      Nitta T, Kanoh H, Inamori K, Suzuki A, Takahashi T, Inokuchi J
    • Journal Title

      Glycobiology

      Volume: 29 Issue: 3 Pages: 260-268

    • DOI

      10.1093/glycob/cwy105

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Plasma membrane sphingomyelin modulates thymocyte development by inhibiting TCR-induced apoptosis2018

    • Author(s)
      Toshima Kaoru、Nagafuku Masakazu、Okazaki Toshiro、Kobayashi Toshihide、Inokuchi Jin-ichi
    • Journal Title

      International Immunology

      Volume: 31 Issue: 4 Pages: 211-223

    • DOI

      10.1093/intimm/dxy082

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] NPC1L1-dependent intestinal cholesterol absorption requires ganglioside GM3 in membrane microdomains2018

    • Author(s)
      Nihei Wataru、Nagafuku Masakazu、Hayamizu Hirotaka、Odagiri Yuta、Tamura Yumi、Kikuchi Yui、Veillon Lucas、Kanoh Hirotaka、Inamori Kei-ichiro、Arai Kenta、Kabayama Kazuya、Fukase Koichi、Inokuchi Jin-ichi
    • Journal Title

      Journal of Lipid Research

      Volume: 59 Issue: 11 Pages: 2181-2187

    • DOI

      10.1194/jlr.m089201

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Deficient ganglioside synthesis restores responsiveness to leptin and melanocortin signaling in obese KKAy mice.2018

    • Author(s)
      Inamori K, Ito H, Tamura Y, Nitta T, Yang X, Nihei W, Shishido F, Imazu S, Tsukita S, Yamada T, Katagiri H, Inokuchi J
    • Journal Title

      Journal of Lipid Research

      Volume: 59 Issue: 8 Pages: 1472-1481

    • DOI

      10.1194/jlr.m085753

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Role of Glycosphingolipids and Glycosphingolipid-Enriched Lipid Rafts in Immunological Functions.2018

    • Author(s)
      Nakayama H, Nagafuku M, Suzuki A, Iwabuchi K, Inokuchi JI.
    • Journal Title

      Methods Mol Biol.

      Volume: 1804 Issue: 23 Pages: 83-95

    • DOI

      10.1002/1873-3468.13275

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Biology of GM3 Ganglioside2018

    • Author(s)
      Inokuchi Jin-ichi、Inamori Kei-ichiro、Kabayama Kazuya、Nagafuku Masakazu、Uemura Satoshi、Go Shinji、Suzuki Akemi、Ohno Isao、Kanoh Hirotaka、Shishido Fumi
    • Journal Title

      Progress in Molecular Biology and Translational Science

      Volume: 156 Pages: 151-195

    • DOI

      10.1016/bs.pmbts.2017.10.004

    • ISBN
      9780128123416
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pharmacological Modulation of Glycosphingolipid Metabolism2018

    • Author(s)
      Inokuchi Jin-ichi、Ode Takashi、Hara-Yokoyama Miki
    • Journal Title

      Progress in Molecular Biology and Translational Science

      Volume: 1804 Pages: 401-410

    • DOI

      10.1007/978-1-4939-8552-4_19

    • ISBN
      9781493985517, 9781493985524
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mass Spectrometry of Gangliosides2018

    • Author(s)
      Suzuki Akemi、Suzuki Minoru、Ito Emi、Nitta Takahiro、Inokuchi Jin-ichi
    • Journal Title

      Progress in Molecular Biology and Translational Science

      Volume: 1804 Pages: 207-221

    • DOI

      10.1007/978-1-4939-8552-4_9

    • ISBN
      9781493985517, 9781493985524
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Insights of Glycosphingolipids function from GM3 synthase deficiency2017

    • Author(s)
      郷 慎司、井ノ口 仁一
    • Journal Title

      生化学

      Volume: 89 Issue: 5 Pages: 644-651

    • DOI

      10.14952/SEIKAGAKU.2017.890644

    • ISSN
      0037-1017
    • Year and Date
      2017-10-25
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of a new B4GalNAcT1 (GM2/GD2/GA2 synthase) isoform, and regulation of enzyme stability and intracellular transport by arginine-based motif2017

    • Author(s)
      Shishido Fumi、Uemura Satoshi、Kashimura Madoka、Inokuchi Jin-ichi
    • Journal Title

      Biochimica et Biophysica Acta (BBA) - Biomembranes

      Volume: 1859 Issue: 10 Pages: 2001-2011

    • DOI

      10.1016/j.bbamem.2017.07.006

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Altered Expression of Ganglioside GM3 Molecular Species and a Potential Regulatory Role During Myoblast Differentiation.2017

    • Author(s)
      Go S, Veillon L, Ciampa M, Mauri L, Sato C, Kitajima K, Prinetti A, Sonnino S, Inokuchi J.
    • Journal Title

      J. Biol. Chem.

      Volume: 292 Issue: 17 Pages: 7040-7051

    • DOI

      10.1074/jbc.m116.771253

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Gangliosides and hearing2017

    • Author(s)
      Inokuchi Jin-ichi、Go Shinji、Yoshikawa Misato、Strauss Kevin
    • Journal Title

      Biochimica et Biophysica Acta (BBA) - General Subjects

      Volume: 1861 Issue: 10 Pages: 2485-2493

    • DOI

      10.1016/j.bbagen.2017.05.025

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Identification of a new liver-specific c-type mRNA transcriptional variant for mouse ST3GAL5 (GM3/GM4 synthase)2017

    • Author(s)
      Shishido Fumi、Uemura Satoshi、Nitta Takahiro、Inokuchi Jin-ichi
    • Journal Title

      Glycoconjugate Journal

      Volume: 34 Issue: 5 Pages: 651-659

    • DOI

      10.1007/s10719-017-9788-1

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] PDMP, a ceramide analogue, acts as an inhibitor of mTORC1 by inducing its translocation from lysosome to endoplasmic reticulum.2017

    • Author(s)
      Takashi O, Katarzyna A. Podyma-Inoue, Kazue T, Jin-ichi I, Toshihide K, Tetsuro W, Yuichi I, Miki Hara-Y.
    • Journal Title

      Experimental Cell Research

      Volume: 350 Issue: 1 Pages: 103-114

    • DOI

      10.1016/j.yexcr.2016.11.011

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] NPC1L1-dependent intestinal cholesterol absorption requires ganglioside GM3 in membrane microdomains.2018

    • Author(s)
      Wataru Nihei, Masakazu Nagafuku, Hirotaka Hayamizu, Yuta Odagiri, Yumi, Tamura, Yui Kikuchi, Lucas Veillon, Hirotaka Kanoh, Kei-ichiro Inamori, Kenta Arai, Kazuya Kabayama, Koichi Fukase, Jin-ichi Inokuchi.
    • Organizer
      10th 2018 Asian Community of Glycoscience and Glycotechnology Conference.
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] New Paradigm for Chronic Inflammation Mediated by Glycosphingolipids.2018

    • Author(s)
      Jin-ichi Inokuchi
    • Organizer
      MicrobiotaMi2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Ganglioside GM3 Molecular Species as Novel Endogenous Ligand for TLR42018

    • Author(s)
      Jin-ichi Inokuchi and Hirotaka Kanoh
    • Organizer
      2nd Japan-Korea Lipid Joint Symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Ganglioside GM3 Molecular Species as Novel Endogenous Ligand for TLR42018

    • Author(s)
      Jin-ichi Inokuchi,
    • Organizer
      24th IUBMB Congress & 15th FAOBMB Congress (IUBMB SEOUL 2018)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] New Paradigm for Chronic Inflammation Mediated by Ganglioside Molecular Species2018

    • Author(s)
      Jin-ichi Inokuchi and Hirotaka Kanoh
    • Organizer
      2018 Gordon Research Conference on “Glycolipid and Sphingolipid Biology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] New Paradigm for Chronic Inflammation Mediated by Ganglioside Molecular Species.2017

    • Author(s)
      Jin-ichi Inokuchi and Hirotaka Kanoh
    • Organizer
      24th International Symposium on Glycoconjugates
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] New Paradigm for Chronic Inflammation Mediated by Ganglioside Molecular Species.2017

    • Author(s)
      Jin-ichi Inokuchi and Hirotaka Kanoh
    • Organizer
      9th Asian Community of Glycoscience and Glycotechnology Conference
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] New Paradigm for Chronic Inflammation Mediated by Ganglioside Molecular Species.2017

    • Author(s)
      Jin-ichi Inokuchi
    • Organizer
      Gordon Research Conference on "Glycolipid and Sphingolipid Biology"
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] スフィンゴミエリン発現の微調整は自己反応性T細胞の除去に関与するか?2017

    • Author(s)
      豊島かおる,永福 正和,岡崎 俊郎,井ノ口仁一
    • Organizer
      日本薬学会第137年会
    • Related Report
      2017 Research-status Report
  • [Presentation] GM3合成酵素ノックアウトマウスは腸管からのコレステロール吸収抑制を介して高コレステロール血症に抵抗性を示す2017

    • Author(s)
      二瓶渉,永福正和,田村友美,稲森啓一郎,新井 健太,樺山 一哉,深瀬 浩一,井ノ口仁一
    • Organizer
      日本薬学会第137年会
    • Related Report
      2017 Research-status Report
  • [Presentation] ガングリオシド欠損による肥満モデルマウスの病態改善および受容体機能に与える影響2017

    • Author(s)
      稲森啓一郎,伊藤英樹,田村有美,楊燕華,二瓶 渉,宍戸 史,突田壮平,山田哲也,片桐秀樹,井ノ口仁一
    • Organizer
      第59回日本脂質生化学会
    • Related Report
      2017 Research-status Report
  • [Presentation] ガングリオシドGM3のアシル鎖構造に基づく新たな自然免疫応答と慢性炎症.2017

    • Author(s)
      狩野裕考,郷慎司,新田 昴大,Lucas Veillon,藤居 真優a,樺山 一哉,下山敦史,深瀬浩一,安藤弘宗,石田秀治,名取良浩,吉村祐一,鈴木 身,井ノ口仁一
    • Organizer
      第59回日本脂質生化学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 胸腺細胞の分化におけるスフィンゴミエリン発現とその機能的役割2017

    • Author(s)
      豊島かおる,永福正和,岡崎俊郎,井ノ口仁一
    • Organizer
      第59回日本脂質生化学会
    • Related Report
      2017 Research-status Report
  • [Presentation] ガングリオシド分子種による慢性炎症応答の新機軸2017

    • Author(s)
      . 井ノ口仁一,狩野裕考
    • Organizer
      第36回日本糖質学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] ガングリオシドはNPC1L1を介した腸管からのコレステロール吸収を制御する2017

    • Author(s)
      二瓶渉,永福正和,狩野裕孝,稲森啓一郎,新井健太,樺山一哉, 深瀬浩一, 井ノ口仁一
    • Organizer
      第36回日本糖質学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] 肥満糖尿病モデルにおけるガングリオシドGM3欠損マウスから得られた新知見.2017

    • Author(s)
      稲森啓一郎,伊藤英樹,田村有美,新田昂大,楊 燕華,二瓶渉,宍戸史,突田壮平,山田哲也,片桐秀樹,井ノ口仁一
    • Organizer
      第11回東北糖鎖研究会・東京糖鎖研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] ガングリオシド分子種による慢性炎症制御の新機軸2017

    • Author(s)
      狩野裕考,郷慎司,新田 昴大,Lucas Veillon,藤居真優,樺山一哉,下山敦史,深瀬浩一,安藤 弘宗,石田秀治,名取良浩,吉村 祐一,鈴木 明身,井ノ口仁一
    • Organizer
      第11回東北糖鎖研究会・東京糖鎖研究会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 細胞膜スフィンゴミエリンは胸腺における自己反応性T細胞の除去に関与するか?2017

    • Author(s)
      豊島かおる,永福正和,岡崎俊郎,井ノ口仁一
    • Organizer
      第11回東北糖鎖研究会・東京糖鎖研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] 慢性炎症によるガングリオシド分子種の発現変化.2017

    • Author(s)
      新田昂大, 狩野 裕考, 郷慎司, Lucas Veillon, 鈴木 明身, 井ノ口仁一
    • Organizer
      第11回東北糖鎖研究会・東京糖鎖研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] ガングリオシドによるNPC1L1を介した腸管からのコレステロール吸収制御.2017

    • Author(s)
      二瓶渉,永福正和,狩野裕孝,稲森啓一郎,新井健太,樺山一哉, 深瀬浩一, 井ノ口仁一
    • Organizer
      第11回東北糖鎖研究会・東京糖鎖研究会
    • Related Report
      2017 Research-status Report
  • [Book] Progress in Molecular Biology and Translational Science (Biology of GM3 Ganglioside in Gangliosides in Health and Disease2018

    • Author(s)
      Inokuchi Jin-ichi、Inamori Kei-ichiro、Kabayama Kazuya、Nagafuku Masakazu、Uemura Satoshi、Go Shinji、Suzuki Akemi、Ohno Isao、Kanoh Hirotaka、Shishido Fumi
    • Total Pages
      455
    • Publisher
      Elsevior
    • Related Report
      2017 Research-status Report
  • [Patent(Industrial Property Rights)] GM3促進炎抑制剤及び炎症性サイトカイン賛成抑制剤2017

    • Inventor(s)
      井ノ口仁一、狩野裕考
    • Industrial Property Rights Holder
      井ノ口仁一、狩野裕考
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2015-232564
    • Filing Date
      2017
    • Related Report
      2017 Research-status Report

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Published: 2017-07-21   Modified: 2020-03-30  

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