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Mechanism and processe of stenoocclusive vascular diseases caused by RNF213 mutation in inflammatory cellular society

Planned Research

Project AreaPreventive medicine through inflammation cellular sociology
Project/Area Number 17H06397
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Complex systems
Research InstitutionKyoto University

Principal Investigator

Koizumi Akio  京都大学, 医学研究科, 名誉教授 (50124574)

Co-Investigator(Kenkyū-buntansha) S Youssefian  京都大学, 医学研究科, 教授 (00210576)
手塚 徹  京都大学, スーパーグローバルコース医学生命系ユニット, 特定講師 (50312319)
土生 敏行  武庫川女子大学, 食物栄養科学部, 准教授 (70346071)
小林 果  三重大学, 医学系研究科, 講師 (70542091)
原田 浩二  京都大学, 医学研究科, 准教授 (80452340)
Project Period (FY) 2017-06-30 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥91,520,000 (Direct Cost: ¥70,400,000、Indirect Cost: ¥21,120,000)
Fiscal Year 2021: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2020: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2019: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2018: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2017: ¥21,320,000 (Direct Cost: ¥16,400,000、Indirect Cost: ¥4,920,000)
Keywords遺伝疫学 / もやもや病 / 感受性遺伝子 / シグナル制御 / RNF213 / ER stress / Apoptosis / R4810K / 細胞分裂 / 腸内細菌 / RNF213-R4810K / Arterial-Stenosis / Mitotic failure / ウイルス抗体の保有状況 / E3 ligase / AAA+ / 循環器疾患 / 脳卒中 / R4810K変異 / 血管閉塞性病変
Outline of Final Research Achievements

We previously identified that RNF213 is a major susceptibility gene for moyamoya disease (MMD) and its founder variant p.R4810K is a risk factor for not only MMD but also several other vascular occlusive diseases. The environmental factors and molecular mechanisms of MMD pathogenesis are largely unknown. To clarify them, in this project, we carried out epidemiological studies focusing on immunological factors in MMD, and elucidated cellular functions of RNF213. Specifically, we analyzed (1) RNF213-mediated signaling pathways involved in vascular occlusion, (2) relevance between mitotic failure and RNF213, (3) roles of RNF213 in response to endoplasmic reticulum (ER) stress, and (4) involvement of viral infection and gut microbiota in MMD pathogenesis.

Academic Significance and Societal Importance of the Research Achievements

本研究により、RNF213が炎症、アポトーシス、小胞体ストレス、細胞分裂、受容体型チロシンキナーゼなど、多様な細胞応答のシグナル制御に関わることが明らかとなった。RNF213の機能解明が進み、もやもや病をはじめとした、RNF213関連血管障害の疾患メカニズムの解明、ひいては、これらの疾患の予防・治療法の構築への貢献が期待できることに、本研究の学術的・社会的な意義がある。また、もやもや病の発症機構を理解する上で、ウィルス感染や腸内細菌叢の関与を精査したことにも意義がある。

Report

(7 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Products Report
  • Research Products

    (41 results)

All 2024 2023 2022 2021 2020 2019 2018 Other

All Int'l Joint Research (6 results) Journal Article (16 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 14 results,  Open Access: 10 results) Presentation (15 results) (of which Int'l Joint Research: 2 results) Book (1 results) Remarks (2 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] Universite Paris Diderot(フランス)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Bordeaux University Hospital(フランス)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Munich Cluster of Systems Neurology/Ludwig-Maximilians-University Munich(ドイツ)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] National University of Ireland Galway(アイルランド)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] McMaster University, Hamilton(カナダ)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Goethe University(ドイツ)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Peripheral blood GATA2 expression impacts RNF213 mutation penetrance and clinical severity in moyamoya disease2024

    • Author(s)
      Yohei Mineharu, Takahiko Kamata, Mei Tomoto, Noriaki Sato, Yoshinori Tamada, Takeshi Funaki, Yuki Oichi, Koji H Harada, Akio Koizumi, Tetsuaki Kimura, Ituro Inoue, Yasushi Okuno, Susumu Miyamoto, and Yoshiki Arakawa
    • Journal Title

      medRxiv

      Volume: June 28

    • DOI

      10.1101/2024.06.22.24306750

    • Related Report
      Products Report
    • Open Access
  • [Journal Article] Posterior cerebral artery involvement in unilateral moyamoya disease is exclusively ipsilateral and influenced by RNF213 mutation gene dose: The SUPRA Japan study2024

    • Author(s)
      Mineharu Yohei、Takagi Yasushi、Koizumi Akio、Morimoto Takaaki、Funaki Takeshi、Hishikawa Tomohito、Araki Yoshio、Hasegawa Hitoshi、Takahashi Jun C.、Kuroda Satoshi、Houkin Kiyohiro、Miyamoto Susumu
    • Journal Title

      Journal of Stroke and Cerebrovascular Diseases

      Volume: 33 Issue: 2 Pages: 107513-107513

    • DOI

      10.1016/j.jstrokecerebrovasdis.2023.107513

    • Related Report
      Products Report
    • Peer Reviewed / Open Access
  • [Journal Article] Moyamoya disease: diagnosis, and interventions2022

    • Author(s)
      Masafumi Ihara, Yumi Yamamoto, Yorito Hattori, Wanyang Liu, Hatasu Kobayashi, Hiroyuki Ishiyama, Takeshi Yoshimoto, Satoru Miyawaki, Tim Clausen, Oh Young Bang, Gary K. Steinberg, Elisabeth Tournier-Lasserve, Akio Koizumi
    • Journal Title

      Lancet Neurology

      Volume: in press

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Lack of association between seropositivity of vasculopathy-related viruses and moyamoya disease.2022

    • Author(s)
      Nakamura Y, Mineharu Y, Kamata T, Funaki T, Susumu M, Koizumi A, Harada HK
    • Journal Title

      J Stroke Cerebrovasc Dis

      Volume: in press

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Suppression of RNF213, a susceptibility gene for moyamoya disease, inhibits endoplasmic reticulum stress through SEL1L upregulation2022

    • Author(s)
      Ahmed Sharif、Habu Toshiyuki、Kim Jiyeong、Okuda Hiroko、Oikawa Shinji、Murata Mariko、Koizumi Akio、Kobayashi Hatasu
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 609 Pages: 62-68

    • DOI

      10.1016/j.bbrc.2022.04.007

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genetic and nongenetic factors for contralateral progression of unilateral moyamoya disease: the first report from the SUPRA Japan Study Group2022

    • Author(s)
      Mineharu Yohei、Takagi Yasushi、Koizumi Akio、Morimoto Takaaki、Funaki Takeshi、Hishikawa Tomohito、Araki Yoshio、Hasegawa Hitoshi、Takahashi Jun C.、Kuroda Satoshi、Houkin Kiyohiro、Miyamoto Susumu
    • Journal Title

      Journal of Neurosurgery

      Volume: 136 Issue: 4 Pages: 1005-1014

    • DOI

      10.3171/2021.3.jns203913

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Characterization of Moyamoya and Middle Cerebral Artery Diseases by Carotid Canal Diameter and RNF213 p.R4810K Genotype2022

    • Author(s)
      Oichi Yuki、Mineharu Yohei、Agawa Yuji、Morimoto Takaaki、Funaki Takeshi、Hitomi Toshiaki、Kobayashi Hatasu、Todo Kenichi、Tani Shoichi、Imamura Hirotoshi、Yoshida Kazumichi、Kataoka Hiroharu、Koizumi Akio、Sakai Nobuyuki、Miyamoto Susumu
    • Journal Title

      Journal of Stroke and Cerebrovascular Diseases

      Volume: 31 Issue: 6 Pages: 106481-106481

    • DOI

      10.1016/j.jstrokecerebrovasdis.2022.106481

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] RNF213 p.R4810K (c.14429G > A) Variant Determines Anatomical Variations of the Circle of Willis in Cerebrovascular Disease2021

    • Author(s)
      Eto Futoshi、Yoshimoto Takeshi、Okazaki Shuhei、Nishimura Kunihiro、Ogura Shiori、Yamaguchi Eriko、Fukuma Kazuki、Saito Satoshi、Washida Kazuo、Koga Masatoshi、Toyoda Kazunori、Morimoto Takaaki、Maruyama Hirofumi、Koizumi Akio、Ihara Masafumi
    • Journal Title

      Frontiers in Aging Neuroscience

      Volume: 13 Pages: 681743-681743

    • DOI

      10.3389/fnagi.2021.681743

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] UBC13 is an RNF213-associated E2 ubiquitin-conjugating enzyme, and Lysine 63-linked ubiquitination by the RNF213UBC13 axis is responsible for angiogenic activity.2021

    • Author(s)
      Habu T, Harada K
    • Journal Title

      FASEB Bioadv.

      Volume: 3 Issue: 4 Pages: 243-258

    • DOI

      10.1096/fba.2019-00092

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Moyamoya disease patient mutations in the RING domain of RNF213 reduce its ubiquitin ligase activity and enhance NFκB activation and apoptosis in an AAA+ domain-dependent manner2020

    • Author(s)
      Takeda Midori、Tezuka Tohru、Kim Minsoo、Choi Jungmi、Oichi Yuki、Kobayashi Hatasu、Harada Kouji H.、Mizushima Tsunehiro、Taketani Shigeru、Koizumi Akio、Youssefian Shohab
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: - Issue: 3 Pages: 668-674

    • DOI

      10.1016/j.bbrc.2020.02.024

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Moyamoya Disease and Spectrums of RNF213 Vasculopathy.2020

    • Author(s)
      Bang OY, Chung JW, Kim DH, Won HH, Yeon JY, Ki CS, Shin HJ, Kim JS, Hong SC, Kim DK, Koizumi A
    • Journal Title

      Translational Stroke Research

      Volume: - Issue: 4 Pages: 580-589

    • DOI

      10.1007/s12975-019-00743-6

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Prevalence of RNF213 p.R4810K Variant in Early-Onset Stroke With Intracranial Arterial Stenosis2019

    • Author(s)
      Kamimura Teppei、Okazaki Shuhei、Morimoto Takaaki、Kobayashi Hatasu、Harada Kouji、Tomita Tsutomu、Higashiyama Aya、Yoshimoto Takeshi、Takahashi Jun C.、Nakagawara Jyoji、Koga Masatoshi、Toyoda Kazunori、Maruyama Hirofumi、Koizumi Akio、Ihara Masafumi
    • Journal Title

      Stroke

      Volume: 50 Issue: 6 Pages: 1561-1563

    • DOI

      10.1161/strokeaha.118.024712

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Moyamoya Disease Susceptibility Variant RNF213 p.R4810K Increases the Risk of Ischemic Stroke Attributable to Large-Artery Atherosclerosis2019

    • Author(s)
      Okazaki S, Koizumi A 他26名(27番目)
    • Journal Title

      Circulation

      Volume: 139 Issue: 2 Pages: 295-298

    • DOI

      10.1161/circulationaha.118.038439

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] EXPRESS: Rare variants in RNF213, a susceptibility gene for moyamoya disease, are found in patients with pulmonary hypertension and aggravate hypoxia-induced pulmonary hypertension in mice2018

    • Author(s)
      Kobayashi Hatasu、Kabata Risako、Kinoshita Hideyuki、Morimoto Takaaki、Ono Koh、Takeda Midori、Choi Jungmi、Okuda Hiroko、Liu Wanyang、Harada Kouji H、Kimura Takeshi、Youssefian Shohab、Koizumi Akio
    • Journal Title

      Pulmonary Circulation

      Volume: - Issue: 3 Pages: 204589401877815-204589401877815

    • DOI

      10.1177/2045894018778155

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dysregulation of RNF213 promotes cerebral hypoperfusion2018

    • Author(s)
      Morimoto T, Enmi J, Hattori Y, Iguchi S, Saito S, Harada K, Okuda H, Mineharu Y, Takagi Y, Youssefian S, Iida H, Miyamoto S, Ihara M, Kobayashi H, Koizumi A.
    • Journal Title

      Sci Rep

      Volume: 8 Issue: 1 Pages: 3607-3607

    • DOI

      10.1038/s41598-018-22064-8

    • NAID

      120006510289

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] もやもや病(ウイリス動脈輪閉塞症)診断・治療ガイドライン(改訂版)2018

    • Author(s)
      冨永悌二, 鈴木則宏, 宮本享, 小泉昭夫, 黒田敏, 高橋淳, 藤村幹, 寶金清博
    • Journal Title

      脳卒中の外科

      Volume: 46 Pages: 1-24

    • NAID

      130006350165

    • Related Report
      2017 Annual Research Report
    • Open Access
  • [Presentation] もやもや病における内頚動脈の直線化は血管狭窄の進行前より存在する2024

    • Author(s)
      峰晴陽平, 阿河祐二, 吉田晴香, 舟木健史, 小泉幸司, 榎直美, 松田晃, 片岡大治, 吉田和道, 原田浩二, 小泉昭夫, 宮本享, 荒川芳輝
    • Organizer
      日本脳卒中学会
    • Related Report
      Products Report
  • [Presentation] 末梢血のGATA2の発現上昇がRNF213変異の浸透率上昇ともやもや病の重症化に関連する2024

    • Author(s)
      峰晴 陽平、鎌田 貴彦、戸本 芽生、佐藤 憲明、玉田 嘉紀、舟木 健史、原田 浩二、木村 哲晃、井上 逸郎, 尾市 雄輝、朴 実樹、笹ヶ迫 知紀、奥野 恭史、宮本 享、荒川 芳輝
    • Organizer
      分子脳神経外科学会
    • Related Report
      Products Report
  • [Presentation] もやもや病患者のiPS細胞由来内皮細胞におけるRNF213変異の影響2022

    • Author(s)
      尾市 雄輝、峰晴 陽平、吉岡 美樹、手塚 徹、Kuan-Chun Lan、藤渕 航、香川 晴信、松本 智子、Knut Woltjen、小泉 昭夫、宮本 享、山下 潤、Shohab Youssefian
    • Organizer
      STROKE 2022
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Effect of RNF213 suppression on endoplasmic reticulum stress2022

    • Author(s)
      Sharif Ahmed, 小林 果, 土生 敏行, 原田 浩二 , 手塚 徹, Shohab Youssefian, 及川 伸二, 村田 真理子, 小泉 昭夫
    • Organizer
      第92回日本衛生学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] もやもや病感受性遺伝子産物RNF213における結合蛋白質の制御機構の解明2021

    • Author(s)
      崔 廷米、手塚 徹、小林 果、原田 浩二、小泉 昭夫、Youssefian Shohab
    • Organizer
      第91回日本衛生学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Rnf213抑制はオスAkitaマウスと異なりメスAkitaマウスの糖尿病を改善しない2021

    • Author(s)
      Sharif Ahmed, 小林 果, 奥田 裕子, 原田 浩二, 土生 敏行, Shohab Youssefian, 及川 伸二, 村田 真理子, 小泉 昭夫
    • Organizer
      第91回日本衛生学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] RNF213 調節不全は両側総頸動脈狭窄マウスモデル の脳低灌流を悪化させる2020

    • Author(s)
      小林 果、森本 貴昭、原田 浩二、奥田 裕子、 Shohab Youssefian、及川 伸二、村田 真理子、 小泉 昭夫
    • Organizer
      第90回日本衛生学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] もやもや病感受性遺伝子産物RNF213 の結合蛋白質 の同定2020

    • Author(s)
      崔 廷米、武田 美都里、小林 果、手塚 徹、 原田 浩二、小泉 昭夫、Youssefian Shohab
    • Organizer
      第90回日本衛生学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 日本人のアテローム血栓性脳梗塞の強力な遺伝子多型RNF213 p.4810K2019

    • Author(s)
      猪原 匡史, 岡崎 周平, 森本 貴昭, 鎌谷 洋一郎, 上村 鉄平, 原田 浩二, 冨田 努, 東山 綾, 高橋 淳, 中川原 譲二, 古賀 政利, 豊田 一則, 鷲田 和夫, 齊藤 聡, 望月 秀樹, 秦 淳, 二宮 利治, 吾郷 哲朗, 久保 充明, 小泉 昭夫
    • Organizer
      第60回日本神経学会学術大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] もやもや病感受性遺伝子産物RNF213のユビキチンリガーゼ活性の検討2019

    • Author(s)
      武田 美都里, 手塚 徹, 金 びん秀, 西出 旭, 崔 廷米, 原田 浩二, 小泉 昭夫, ショハブ・ユーセフィアン
    • Organizer
      第89回日本衛生学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] もやもや病感受性遺伝子RNF213の結合分子の同定2019

    • Author(s)
      崔 廷米, 井上 令一, 武田 美都里, 小林 果, 手塚 徹, 原田 浩二, 小泉 昭夫, Youssefian Shohab
    • Organizer
      第89回日本衛生学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Rnf213遺伝子改変マウスにおける免疫細胞・血清サイトカインの系統的解析2019

    • Author(s)
      小林 果, 西村 泰光, 奥田 裕子, 原田 浩二, 加畑 理咲子, 武田 美都里, 崔 廷米, Youssefian Shohab, 大槻 剛巳, 小泉 昭夫
    • Organizer
      第89回日本衛生学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] mysterin 遺伝子の肺高血圧症患者遺伝子スクリーニングおよびマウスモデルによる解析2018

    • Author(s)
      小林果、加畑理咲子、木下秀之、森本貴昭、武田美都里、崔廷米、奥田裕子、原田浩二、Youssefian Shohab、小泉昭夫
    • Organizer
      第88回 日本衛生学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] もやもや病タンパク質RNF213 のE3 ligase活性の機能的評価2018

    • Author(s)
      武田美都里、キム ミンソ、小林果、原田浩二、土生敏行、小泉昭夫、ユーセフィアン ショハブ
    • Organizer
      第88回 日本衛生学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] The Prevalence of RNF213 p.R4810K Variant is High in Juvenile-Onset Stroke Patients With Intracranial Arterial Stenosis2018

    • Author(s)
      Teppei Kamimura, Shuhei Okazaki, Takaaki Morimoto, Hatasu Kobayashi, Kouji Harada, Tsutomu Tomita, Aya Higashiyama, Jun C Takahashi, Jyoji Nakagawara, Kazunori Toyoda, Akio Koizumi, Masafumi Ihara
    • Organizer
      International Stroke Conference 2018
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Book] Moyamoya Disease: Current Knowledge and Future Perspectives2021

    • Author(s)
      Hatasu Kobayashi, Kouji H. Harada, Toshiyuki Habu, Yasuhisa Nakamura, Jiyeong Kim, Akio Koizumi
    • Total Pages
      341
    • Publisher
      Springer Singapore
    • Related Report
      2020 Annual Research Report
  • [Remarks] 炎症細胞社会の中でのRNF213変異によるかく乱と血管閉塞性病変形成の解明

    • URL

      http://plaza.umin.ac.jp/khh/gene-epi/

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
  • [Remarks] 炎症細胞社会の中でのRNF213変異によるかく乱と血管閉塞性病変形成の解明

    • URL

      http://hes.med.kyoto-u.ac.jp/gene-epi/index.html

    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] もやもや病の発症を予測する方法2023

    • Inventor(s)
      峰晴陽平、小泉昭夫、宮本享、奥野恭史
    • Industrial Property Rights Holder
      京都大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2023-150115
    • Filing Date
      2023
    • Related Report
      Products Report

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Published: 2017-07-04   Modified: 2025-03-27  

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