愛情ホルモン・オキシトシンによる炎症免疫抑制作用の分子基盤の解明

• Project/Area Number: 21H02695
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Kanazawa University
• Principal Investigator: 山本 靖彦 金沢大学, 医学系, 教授 (20313637)
• Co-Investigator(Kenkyū-buntansha): 棟居 聖一 金沢大学, 医学系, 助教 (10399040) ; 木村 久美 金沢大学, 医学系, 助教 (60409472) ; 松下 貴史 金沢大学, 医学系, 教授 (60432126)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2023: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2022: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2021: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: オキシトシン / 制御性B細胞 / 炎症

Outline of Research at the Start

オキシトシンの炎症抑制効果について、特に、B細胞集団の中で免疫反応を抑制する制御性B細胞の分化誘導に注目し、全身性エリテマトーデスマウスモデルを用いて研究を進める。オキシトシンによる炎症免疫抑制作用や自己抗体産生抑制効果について、オキシトシン受容体依存的な観点から追究するとともに、オキシトシン受容体によらない非依存的経路についても研究を進め、その全貌を解明することで新しい概念を提唱する。

Outline of Annual Research Achievements

オキシトシンは、脳視床下部の室傍核と視索上核の神経細胞で合成されるペプチドホルモンであり、その軸索のある下垂体後葉から循環血液中に放出され、陣痛誘発時の子宮収縮や授乳時の乳汁分泌に関わることは以前より分かっていた。最近では、中枢神経作用である信頼や愛情の形成に関わったり、抗炎症作用や免疫抑制効果についても知られるようになってきた。しかし、その分子作用メカニズムに関してまだまだ不明な点が多い。本研究では、そのようなオキシトシンの免疫制御作用について、オキシトシン受容体依存的な観点から研究を進めるとともに、オキシトシン受容体非依存的な効果についても調べ、その分子機構の全貌を明らかにすることを目的とする。
まず、炎症への効果として、全身性エリテマトーデス（SLE）マウスモデル（MRL/lprマウス）を使って、オキシトシン持続投与による有効性を調べると、全身のリンパ節腫脹、皮膚の炎症、腎炎の病態が軽減し、抗dsDNA抗体や抗ssDNA抗体、抗核抗体などの自己抗体価も低下するなどの効果があった。免疫細胞において、オキシトシン受容体の発現を調べと、オキシトシン受容体の発現は一部のB細胞サブセットで確認できた。MRL/lprマウスの遺伝背景に、オキシトシン受容体欠損を導入したマウスを作製し、病態を解析すると、骨髄におけるB細胞分化が障害され、末梢血中のB細胞画分の低下が認められた。予想に反した表現系であったが、オキシトシン受容体シグナルは、骨髄におけるB細胞の分化、形質細胞への分化と自己抗体産生抑制B細胞分化に関わることが分かった。
また、オキシトシン受容体非依存的な効果として、オキシトシンに結合する補体C4を同定し、血中でのオキシトシン輸送担体として働いていることを見出した。現在、補体C4がオキシトシンの養育行動・社会性行動や抗炎症作用などへどのような影響を与えているか調べている。

Research Progress Status

令和5年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和5年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Harvard Medical School(米国)
• [Int'l Joint Research] 順天郷大学(韓国)
• [Int'l Joint Research] Harvard Medical School(米国)
• [Int'l Joint Research] 順天郷大学校(韓国)
• [Int'l Joint Research] Harvard Medical School(米国)
• [Int'l Joint Research] 順天郷大学校(韓国)
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  • Journal Title: Cancer Sci. Volume: 113 Issue: 10 Pages: 3376-3389
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  • Author(s): Tsubokawa Daigo、Kikuchi Taisei、Lee Jae Man、Kusakabe Takahiro、Yamamoto Yasuhiko、Maruyama Haruhiko
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  • Peer Reviewed / Open Access
• [Journal Article] An improved sample extraction method reveals that plasma receptor for advanced glycation end-products (RAGE) modulates circulating free oxytocin in mice (2021)
  • Author(s): Cherepanov Stanislav M.、Gerasimenko Maria、Yuhi Teruko、Shabalova Anna、Zhu Hong、Yokoyama Shigeru、Salmina Alla B.、Munesue Shei-ichi、Harashima Ai、Yamamoto Yasuhiko、Higashida Haruhiro
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• [Journal Article] Glycation reaction and the role of the receptor for advanced glycation end-products in immunity and social behavior (2020)
  • Author(s): Leerach Nontaphat、Harashima Ai、Munesue Seiichi、Kimura Kumi、Oshima Yu、Goto Hisanori、Yamamoto Hiroshi、Higashida Haruhiro、Yamamoto Yasuhiko
  • Journal Title: Glycoconjugate Journal Volume: in press Issue: 3 Pages: 303-310
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• [Presentation] 終末糖化産物受容体(RAGE)はメタボリックシンドロームにおける認知機能障害の病態に関与する (2023)
  • Author(s): 三好晶雄, 叶大森, 牛谷友栄, 角谷学, 小西康輔, 庄司拓仁, 安田好文, 黒田悦史, 北岡志保, 八木秀司、山本靖彦、小山 英則
  • Organizer: 日本内分泌学会
• [Presentation] esRAGEによって潜在的な慢性炎症による認知障害は回復する (2023)
  • Author(s): 叶大森, 三好晶雄, 牛谷友栄, 角谷学, 小西康輔, 庄司拓仁, 北岡志保, 黒田悦史, 八木 秀司, 山本靖彦、小山英則
  • Organizer: 日本糖尿病学会
• [Presentation] 糖尿病合併症の成因に関する最近の知見～糖化反応（グリケーション）～ (2023)
  • Author(s): 山本靖彦
  • Organizer: 第38回日本糖尿病合併症学会
  • Invited
• [Presentation] NAFLD疾患感受性遺伝子としてのオキシトシン受容体の遺伝子多型 (2023)
  • Author(s): 後藤久典、山本靖彦、辻口博聖、竹下有美枝、田中健雄、中野雄二郎、田嶋敦、中村裕之、篁 俊成
  • Organizer: 第38回日本糖尿病合併症学会
• [Presentation] RAGEを介したヒト骨肉腫細胞悪性化の分子機構の解明 (2023)
  • Author(s): 棟居聖一、武内章彦、原島 愛、木村久美、大島由、Wah Wah Aung、田中麻莉子、Yupa Srithongchai、桜井彩那、山本靖彦
  • Organizer: 日本メイラード学会
• [Presentation] 超深堀！ 糖化と疾患 (2023)
  • Author(s): 山本靖彦
  • Organizer: 第43回日本眼薬理学会
  • Invited
• [Presentation] Glycation reaction and the receptor for advanced glycation end-products (RAGE): foe or friend for life? (2023)
  • Author(s): 山本靖彦
  • Organizer: 22nd IUNS-ICN
  • Int'l Joint Research / Invited
• [Presentation] 『転ばぬ先の知恵』 全身疾患に関わる知恵 (2023)
  • Author(s): 山本靖彦
  • Organizer: 第127回日本眼科学会総会
  • Invited
• [Presentation] 食と愛情発露：RAGEを介したオキシトシン輸送サポート (2023)
  • Author(s): 山本靖彦
  • Organizer: 第26回 糖化ストレス研究会
  • Invited
• [Presentation] グリケーション研究で病気がみえる (2023)
  • Author(s): 山本靖彦
  • Organizer: 第96回日本生化学会
  • Invited
• [Presentation] グリケーションと糖尿病合併症 (2023)
  • Author(s): 山本靖彦
  • Organizer: 第37回日本糖尿病・肥満動物学会
  • Invited
• [Presentation] グリケーションからみる最新血管生物学 (2022)
  • Author(s): 原島 愛、山本靖彦
  • Organizer: 第95回日本生化学会大会
  • Invited
• [Presentation] 老化に関わる糖化研究から愛情のサイエンスへの展開 (2022)
  • Author(s): 山本靖彦
  • Organizer: 分子病理学会
  • Invited
• [Presentation] 糖化と全身疾患について-グリケーション研究の最前線 (2022)
  • Author(s): 山本靖彦
  • Organizer: 第22回日本抗加齢学会総会
  • Invited
• [Presentation] Glycation reaction and the receptor for advanced glycation end-products (RAGE): foe or friend for life? (2022)
  • Author(s): Yasuhiko Yamamoto
  • Organizer: 22nd IUNS-ICN
  • Int'l Joint Research / Invited
• [Presentation] 『転ばぬ先の知恵』全身疾患に関わる知恵 (2022)
  • Author(s): 山本靖彦
  • Organizer: 第127回日本眼科学会総会
  • Invited
• [Presentation] Understanding glycation and RAGE in diabetes and beyond (2022)
  • Author(s): Yasuhiko Yamamoto
  • Organizer: 4th MHRC Symposium at SIMS
  • Int'l Joint Research / Invited
• [Presentation] Oxytocin, RAGE and maternal bonding (2022)
  • Author(s): Yasuhiko Yamamoto
  • Organizer: The International Conference Social Brain-Focus on Emotions
  • Int'l Joint Research / Invited
• [Presentation] グリケーションとその最終産物受容体RAGE：病態形成における意義について (2021)
  • Author(s): 棟居聖一、山本靖彦
  • Organizer: 第94回日本生化学会シンポジウム
  • Invited
• [Book] Medical BIOCHEMISTRY, SIXTH EDITION (2024)
  • Author(s): John W. Baynes, Marek H. Dominiczak
  • Total Pages: 2812
  • Publisher: Elsevier
  • ISBN: 9780323834506
• [Remarks] 金沢大学大学院医薬保健学総合研究科医学専攻血管分子生物学HP
  • URL: https://biochem2.w3.kanazawa-u.ac.jp/