Identification of molecular mechanisms of RNF213-related occlusive cerebrovascular diseases and development of new treatment strategies

• Project/Area Number: 19H03770
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Kyoto University
• Principal Investigator: Miyamoto Susumu 京都大学, 医学研究科, 教授 (70239440)
• Co-Investigator(Kenkyū-buntansha): 高橋 淳 京都大学, iPS細胞研究所, 教授 (10270779) ; 片岡 大治 国立研究開発法人国立循環器病研究センター, 病院, 部長 (40359815) ; 山下 潤 京都大学, iPS細胞研究所, 教授 (50335288) ; 峰晴 陽平 京都大学, 医学研究科, 特定准教授 (50716602) ; 小泉 昭夫 京都大学, 医学研究科, 名誉教授 (50124574)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2021: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2020: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2019: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: moyamoya / genetics / iPS cells / cerebrovascular disease / atherosclerosis / moyamoya disease / RNF213 / iPS / gene editing / 閉塞性血管障害 / 遺伝子変異 / 血管平滑筋細胞 / 血管内皮細胞 / もやもや病 / 感受性遺伝子 / iPSモデル / 遺伝子改変マウス / CFD

Outline of Research at the Start

動脈硬化以外の主幹動脈狭窄のメカニズムは未解明な点が多い。この病態を解明し、予防法を確立することは、国民の健康増進に大きく寄与する。本研究では、主幹動脈狭窄の感受性遺伝子RNF213と最近特定した第2の感受性因子MMDX遺伝子について、①2つの遺伝子の相互作用を含めた分子機序の解明、②iPS由来の血管内皮細胞、血管平滑筋とリンパ球に対する2つの遺伝子の影響の解明と細胞を用いた治療薬のスクリーニング、③動物モデルの確立と治療薬の効果検証、④血行力学的ストレスの影響の解明とComputational fluid dynamics（CFD）を利用した発症予測可能性について検証する。

Outline of Final Research Achievements

(1) We compared the characteristics of endothelial cells differentiated from patient-derived mutant iPS cells and their genetically repaired cell lines, and identified molecules that are responsible for differential tube formation capacity. (2) We compared gene expression in blood from patients and carriers with the RNF213 p.R4810K mutation and identified molecules that facilitate the progression of moyamoya disease. (3) We identified daily alcohol drinking as a risk factor for contralateral progression of unilateral moyamoya disease and clarified the association of several environmental factors including viral infection. (4) We clarified the effect of p.R4810K mutation on the morphology and hemodynamics of intracranial arteries in patients with moyamoya disease. These findings will facilitate the development of disease models, which is critical to understand the pathogenesis of the disease.

Academic Significance and Societal Importance of the Research Achievements

RNF213 p.R4810K変異は東アジアのもやもや病患者で最も多く認められる変異にも関わらず、その詳細な機能は不明であった。本研究で樹立したiPS細胞の遺伝子修復株はその詳細な機能解明に貢献できると考えられる。実際に、内皮細胞における変異の影響が本研究で明らかになり、今後は疾患モデル樹立により、病態解明の他、治療法開発にも繋がると期待される。p.R4810K変異は、もやもや病以外にも数多くの頭蓋内外の血管障害に関与しており、その機能解明は、非動脈硬化性血管障害の病態解明と治療開発にも貢献できると考えられる。

Research Products

• [Journal Article] Genetic and nongenetic factors for contralateral progression of unilateral moyamoya disease: the first report from the SUPRA Japan Study Group (2022)
  • 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
  • Peer Reviewed
• [Journal Article] Characterization of Moyamoya and Middle Cerebral Artery Diseases by Carotid Canal Diameter and RNF213 p.R4810K Genotype (2022)
  • 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
  • Peer Reviewed
• [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, Miyamoto S, Koizumi A, Harada HK.
  • Journal Title: J Stroke Cerebrovasc Dis Volume: -
  • Peer Reviewed
• [Journal Article] Plasticity of the bony carotid canal and its clinical use for assessing negative remodeling of the internal carotid artery (2021)
  • Author(s): Oichi Yuki、Mineharu Yohei、Agawa Yuji、Morimoto Takaaki、Funaki Takeshi、Fushimi Yasutaka、Yoshida Kazumichi、Kataoka Hiroharu、Miyamoto Susumu
  • Journal Title: PLOS ONE Volume: 16 Issue: 12 Pages: e0261235-e0261235
  • DOI: 10.1371/journal.pone.0261235
  • Peer Reviewed / Open Access
• [Journal Article] RNF213 and GUCY1A3 in Moyamoya Disease: Key Regulators of Metabolism, Inflammation, and Vascular Stability (2021)
  • Author(s): Mineharu Yohei、Miyamoto Susumu
  • Journal Title: Frontiers in Neurology Volume: 12 Pages: 687088-687088
  • DOI: 10.3389/fneur.2021.687088
  • Peer Reviewed
• [Journal Article] Genetic and non-genetic factors for contralateral progression of unilateral moyamoya disease：the first report from the SUPRA Japan Study Group (2021)
  • Author(s): Mineharu Y, Takagi Y, Koizumi A, Morimoto T, Funaki T, Hishikawa T, Araki Y, Hasegawa H, Takahashi JC, Kuroda S, Houkin K, and Miyamoto S: on behalf of the SUPRA Japan Study Group.
  • Journal Title: Journal of Neurosurgery Volume: in press
  • Peer Reviewed
• [Journal Article] Cortical Distribution of Fragile Periventricular Anastomotic Collateral Vessels in Moyamoya Disease: An Exploratory Cross-Sectional Study of Japanese Patients with Moyamoya Disease (2020)
  • Author(s): Akinori Miyakoshi, Takeshi Funaki, Yasutaka Fushimi, Takuro Nakae, Masakazu Okawa, Takayuki Kikuchi, Hiroharu Kataoka, Kazumichi Yoshida, Yohei Mineharu, Masao Matsuhashi, Eiji Nakatani, Susumu Miyamoto
  • Journal Title: AJNR Am J Neuroradiol Volume: 41 Issue: 12 Pages: 2243-2249
  • DOI: 10.3174/ajnr.a6861
  • Peer Reviewed / Open Access
• [Journal Article] Revascularization Surgery in Childhood Associated with a Low Incidence of Microbleeds in Adult Patients with Moyamoya (2020)
  • Author(s): Yamao Yukihiro、Takahashi Jun C.、Funaki Takeshi、Mineharu Yohei、Kikuchi Takyuki、Okada Tomohisa、Togashi Kaori、Miyamoto Susumu
  • Journal Title: World Neurosurgery Volume: 133 Pages: e716-e721
  • DOI: 10.1016/j.wneu.2019.09.144
  • Peer Reviewed
• [Journal Article] もやもや病 (2020)
  • Author(s): 舟木健史、峰晴陽平、宮本享
  • Journal Title: 生命の科学 Volume: 71 Pages: 484-485
• [Presentation] 片側もやもや病のPCA狭窄とRNF213遺伝子変異および転帰との関連 (2022)
  • Author(s): 峰晴陽平、 高木康志、小泉昭夫、森本貴昭、舟木健史、菱川朋人、荒木芳生、長谷川仁、高橋淳、黒田敏、寶金清博、宮本享
  • Organizer: 日本脳卒中学会
• [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: 日本脳卒中学会
• [Presentation] 片側もやもや病のPCA狭窄とRNF213遺伝子変異および転帰との関連 (2021)
  • Author(s): 峰晴陽平、 高木康志、小泉昭夫、森本貴昭、舟木健史、菱川朋人、荒木芳生、長谷川仁、高橋淳、黒田敏、寶金清博、宮本享
  • Organizer: 日本脳神経外科学会総会
• [Presentation] 頚動脈管の可塑性と内頚動脈リモデリング評価への臨床応用 (2021)
  • Author(s): 尾市 雄輝、峰晴 陽平、阿河 祐二、森本 貴昭、舟木 健史、伏見 育崇、吉田 和道、片岡 大治、宮本 享
  • Organizer: 日本脳神経外科学会総会
• [Presentation] もやもや病治療のこれから：メカニズム解明に基づいた診断と治療の発展 (2020)
  • Author(s): 峰晴陽平、舟木健史、片岡大治、吉田和道、菊池隆幸、大川将和、山尾幸広、高橋 淳、 髙木康志、 宮本享
  • Organizer: 日本脳神経外科学会総会
  • Invited
• [Presentation] Future medical application of single cell analysis. (2020)
  • Author(s): Mineharu, Y.
  • Organizer: International Symposium on Micro-NanoMechatronics and Human Science
  • Int'l Joint Research / Invited
• [Presentation] Significance of RNF213 in tumorgenicity of medulloblastoma. (2020)
  • Author(s): Mineharu Y, Oichi Y, Kamata T, Matsui Y, Morimoto T, Tanji M, Kobayashi H, Okuda H, Harada KH, Koizumi A, Arakawa Y and Miyamoto S.
  • Organizer: International Symposium on Pediatric Neuro-Oncology
  • Int'l Joint Research
• [Presentation] 片側もやもや病の遺伝的要因を含めた対側進行のリスク評価． (2020)
  • Author(s): 峰晴 陽平、高木 康志、小泉 昭夫、森本 貴昭、舟木 健史、菱川 朋人、荒木 芳生、長谷川 仁、高橋 淳、黒田 敏、寳金 清博、宮本 享．
  • Organizer: 日本脳神経外科学会総会
• [Presentation] もやもや病の末梢血バイオマーカーの開発：IL-1β誘導性プロスタグランジンE合成酵素のmRNA精密定量計測 (2020)
  • Author(s): 峰晴陽平、三橋将人、坂井信幸、宮本享
  • Organizer: 日本脳卒中学会
• [Book] Moyamoya Disease: Current Knowledge and Future Perspectives (2020)
  • Author(s): Mineharu Y, Miyamoto S
  • Total Pages: 341
  • Publisher: Springer
• [Remarks] 教育研究活動データベース
  • URL: https://kyouindb.iimc.kyoto-u.ac.jp/j/qZ6mH