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Development of novel treatment approach for diabetic polyneuropathy targeting RAGE signaling and macrophage polarization

Research Project

Project/Area Number 18K16220
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 54040:Metabolism and endocrinology-related
Research InstitutionHirosaki University

Principal Investigator

Osonoi Sho  弘前大学, 医学研究科, 客員研究員 (40816261)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords糖尿病性神経障害 / マクロファージ / 終末糖化産物 / RAGE / 軸索輸送 / 逆行性軸索輸送 / インスリンシグナル / AGR-RAGEシグナル / AGEs(終末糖化産物)
Outline of Final Research Achievements

Radical treatment for diabetic neuropathy (DPN) has not been established. In this study, we focused on the signaling of advanced glycation end products and their receptors, RAGE, and macrophage-mediated inflammation as pathological mechanisms for novel therapeutic targets. Diabetic RAGE-deficient mice and diabetic bone marrow cell-specific RAGE-deficient mice, which lack macrophage RAGE, showed reduced development and progression of DPN. Through detailed analysis, we elucidated the pathological mechanism by which activation of RAGE signaling induces macrophages infiltrating peripheral nerves to differentiate into pro-inflammatory phenotype and induces neuropathy through decreased insulin sensitivity of nerves by inflammatory cytokines and impaired axonal transport.

Academic Significance and Societal Importance of the Research Achievements

今回の研究により、マクロファージにおけるRAGEシグナルがDPNの発症・進展に関与し、その抑制がDPNの新規治療法となる可能性が示された。DPNは最も有病率が高く、早期に発症する糖尿病性合併症であり、進行期には下肢の壊疽や心臓血管自律神経障害の合併により予後を左右する。有効な治療法を開発することで患者のQOLや予後の改善、医療経済負担の削減が期待される。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (18 results)

All 2021 2020 2019 2018

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 2 results) Presentation (14 results) (of which Int'l Joint Research: 3 results,  Invited: 2 results)

  • [Journal Article] Biphasic changes in β-cell mass around parturition are accompanied by increased serotonin production2020

    • Author(s)
      Takahashi Masaya、Miyatsuka Takeshi、Suzuki Luka、Osonoi Sho、Himuro Miwa、Miura Masaki、Katahira Takehiro、Wakabayashi Yuka、Fukunaka Ayako、Nishida Yuya、Fujitani Yoshio、Takeda Satoru、Mizukami Hiroki、Itakura Atsuo、Watada Hirotaka
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 4962-4962

    • DOI

      10.1038/s41598-020-61850-1

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Diabetes, an independent poor prognostic factor of non-B non-C hepatocellular carcinoma, correlates with dihydropyrimidinase-like 3 promoter methylation.2020

    • Author(s)
      Umetsu S, Mizukami H, Saito T, Uchida C, Igawa A, Kudo K, Itabashi C, Osonoi S, Danyang G, Sasaki T, Yagihashi S, Hakamada K.
    • Journal Title

      Sci Rep

      Volume: 10 Issue: 1 Pages: 1156-1156

    • DOI

      10.1038/s41598-020-57883-1

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Serotonin Regulates Adult β-Cell Mass by Stimulating Perinatal β-Cell Proliferation2019

    • Author(s)
      Moon Joon Ho、Kim Yeong Gi、Kim Kyuho、Osonoi Sho、Wang Shuang、Saunders Diane C.、Wang Juehu、Yang Katherine、Kim Hyeongseok、Lee Junguee、Jeong Ji-Seon、Banerjee Ronadip R.、Kim Seung K.、Wu Yingjie、Mizukami Hiroki、Powers Alvin C.、German Michael S.、Kim Hail
    • Journal Title

      Diabetes

      Volume: 69 Issue: 2 Pages: 205-214

    • DOI

      10.2337/db19-0546

    • NAID

      40022434505

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Normal High HbA1c a Risk Factor for Abnormal Pain Threshold in the Japanese Population2019

    • Author(s)
      Itabashi Chieko、Mizukami Hiroki、Osonoi Sho、Takahashi Kazuhisa、Kudo Kazuhiro、Wada Kanichiro、Inaba Wataru、Danyang Guo、Uchida Chiaki、Umetsu Satoko、Igawa Akiko、Ogasawara Saori、Ryuzaki Masaki、Komeda Kouji、Ishibashi Yasuyuki、Yagihashi Soroku、Nakaji Shigeyuki
    • Journal Title

      Frontiers in Endocrinology

      Volume: 10

    • DOI

      10.3389/fendo.2019.00651

    • Related Report
      2019 Research-status Report
  • [Presentation] RAGE-Dependent Macrophage Activation Aggravates Retrograde Axonal Transport via Attenuated Insulin Signaling of Peripheral Nerves in Experimental Diabetic Polyneuropathy2021

    • Author(s)
      Sho Osonoi
    • Organizer
      American Diabetes Association 81th Scientific Sessions
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 糖尿病性神経障害においてRAGEシグナルはマクロファージを活性化し末梢神経のインスリン抵抗性と逆行性軸索輸送障害 を惹起する2021

    • Author(s)
      遅野井 祥
    • Organizer
      第64回日本糖尿病学会年次学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] マクロファージのRAGEシグナルは糖尿病性神経障害の発症、進展に関与している2020

    • Author(s)
      遅野井 祥
    • Organizer
      第35回日本糖尿病合併症学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Deficit of Retrograde Axonal Transportation Was Mediated via Activation of Macrophage RAGE Signaling in Experimental Diabetic Polyneuropathy2019

    • Author(s)
      Sho Osonoi, Hiroki Mizukami, Saori Ogasawara, Kazunori Sango, Kazuhisa Takahashi, Yasuhiko Yamamoto, Hiroshi Yamamoto, Soroku Yagihashi
    • Organizer
      American Diabetes Association 79th Scientific Sessions
    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] RAGE欠損マウスは抗炎症性マクロファージ優位の浸潤により糖尿病性神経障害の発症が抑制される2019

    • Author(s)
      遲野井 祥,水上 浩哉,進藤 陸生,高橋 和久,小笠原 早織,三五 一憲,山本 靖彦,山本 博,八木橋 操六
    • Organizer
      第108回 日本病理学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 糖尿病性神経障害の病期と病態2019

    • Author(s)
      遅野井 祥,水上 浩哉
    • Organizer
      第34回日本糖尿病合併症学会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 糖尿病性神経障害におけるM1マクロファージ浸潤は逆行性軸索輸送を減弱させる2019

    • Author(s)
      遲野井 祥,水上 浩哉,進藤 陸生,高橋 和久,小笠原 早織,三五 一憲,山本 靖彦,山本 博,八木橋 操六
    • Organizer
      第62回 日本糖尿病学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] 糖尿病性神経障害ではRAGE依存性炎症により坐骨神経逆行性軸索輸送が障害される2019

    • Author(s)
      遲野井 祥,水上 浩哉,進藤 陸生,佐々木 崇矩,高橋 和久,小笠原 早織,三五 一憲,山本 靖彦,山本 博,八木橋 操六
    • Organizer
      令和元年度糖尿病性神経障害を考える会
    • Related Report
      2019 Research-status Report
  • [Presentation] 糖尿病性神経障害におけるM1マクロファージ浸潤は逆行性軸索輸送を減弱させる2019

    • Author(s)
      遲野井 祥,水上 浩哉,高橋 和久,小笠原 早織,三五 一憲,山本 靖彦,山本 博,八木橋 操六
    • Organizer
      第62回日本糖尿病学会年次学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 演題名未定(糖尿病性神経障害における急性期の病態について)2019

    • Author(s)
      遲野井 祥,水上 浩哉,高橋 和久,小笠原 早織,三五 一憲,山本 靖彦,山本 博,八木橋 操六
    • Organizer
      第33回日本糖尿病合併症学会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] RAGEシグナルは糖尿病性神経障害における坐骨神経逆行性輸送に関与する2019

    • Author(s)
      遲野井 祥,水上 浩哉,高橋 和久,小笠原 早織,三五 一憲,山本 靖彦,山本 博,八木橋 操六
    • Organizer
      第33回日本糖尿病・肥満動物学会年次学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Suppression of Neuropathy Development in Diabetic Rage-Deficient Mice Is Associated with Absence of M1/M2 Macrophage Skewing in the Sciatic Nerve2018

    • Author(s)
      Sho Osonoi, Hiroki Mizukami, Saori Ogasawara, Kazunori Sango, Kazuhisa Takahashi, Yasuhiko Yamamoto, Hiroshi Yamamoto, Soroku Yagihashi
    • Organizer
      American Diabetes Association 78th Scientific Sessions
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 糖尿病性神経障害におけるマクロファージ浸潤とDRGニューロン萎縮の関係について2018

    • Author(s)
      遲野井 祥,水上 浩哉,高橋 和久,小笠原 早織,三五 一憲,山本 靖彦,山本 博,八木橋 操六
    • Organizer
      第61回日本糖尿病学会年次学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 糖尿病性神経障害における浸潤マクロファージ極性とDRGニューロンの萎縮の関係について2018

    • Author(s)
      遲野井 祥,水上 浩哉,高橋 和久,小笠原 早織,三五 一憲,山本 靖彦,山本 博,八木橋 操六
    • Organizer
      第32回日本糖尿病合併症学会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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