Mechanisms of moyamoya-susceptible gene expression by interferon and the establishment of preventive medicine for cerebrovascular disease

• Project/Area Number: 26460801
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hygiene and public health
• Research Institution: St. Marianna University School of Medicine (2015-2016); Kyoto University (2014)
• Principal Investigator: Hitomi Toshiaki 聖マリアンナ医科大学, 医学部, 准教授 (90405275)
• Co-Investigator(Kenkyū-buntansha): 小泉 昭夫 京都大学, 医学研究科, 教授 (50124574) ; 小林 果 京都大学, 医学研究科, 特定講師 (70542091)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 予防医学 / もやもや病 / mysterin（RNF213） / インターフェロン / 脳血管疾患 / 血管内皮細胞 / iPS細胞 / 感染症 / Mysterin（RNF213） / R4810K / Mysterin / RNF213 / 疾患iPS細胞

Outline of Final Research Achievements

Mysterin (RNF213) is a susceptibility gene for moyamoya disease (MMD) and its coding variant, p.R4810K, is a common founder variant in East Asian countries. Several angiogenic and anti-angiogenic factors [including interferons (IFNs), IFN-β and IFN-γ] induced transcriptional expression of mysterin in human umbilical vein endothelial cells (HUVECs). In HUVECs, upregulation of mysterin by IFN-β is mediated by a STAT1-binding site on the mysterin gene promoter. The anti-angiogenic activities of IFN-β are partially rescued by siRNA for STAT1, and completely rescued by siRNA for mysterin. Treatment with IFN-β induced mysterin mRNA and decreased angiogenesis in induced pluripotent stem cells-derived vascular endothelial cells (iPSECs) derived from control subjects and patients with MMD. Our data suggest that mysterin mediates the IFN-β anti-angiogenic signaling pathway; MMD may impair angiogenesis in patients with infectious or autoimmune disease.

Research Products

• [Journal Article] A new horizon of moyamoya disease and associated health risks explored through RNF213. (2016)
  • Author(s): Koizumi A, Kobayashi H, Hitomi T, Harada KH, Habu T, Youssefian S.
  • Journal Title: Environ Health Prev Med. Volume: 21(2) Issue: 2 Pages: 55-70
  • DOI: 10.1007/s12199-015-0498-7
  • NAID: 120005973383
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Infantile pain episodes associated with novel Nav1.9 mutations in familial episodic pain syndrome in Japanese families (2016)
  • Author(s): Hiroko Okuda, Atsuko Noguchi, Hatasu Kobayashi, Daiki Kondo, Kouji H.Harada, Shohab Youssefian, Hirotomo Shioi, Risako kabata, Yuki Domon,Kazufumi Kubota, Yutaka Kitano, Yasunori Takayama, Toshiaki Hitomi,Kousaku Ohno, Yoshiaki Saito, Takeshi Asano, Makoto Tominaga, Tsutomu Takahashi, and Akio Koizumi.
  • Journal Title: PLOS ONE Volume: 11 Issue: 5 Pages: e0154827-e0154827
  • DOI: 10.1371/journal.pone.0154827
  • NAID: 120005946996
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia. (2016)
  • Author(s): Banh RS, Iorio C, Marcotte R, Xu Y, Cojocari D, Rahman AA, Pawling J, Zhang W, Sinha A, Rose CM, Isasa M, Zhang S, Wu R, Virtanen C, Hitomi T, Habu T, Sidhu SS, Koizumi A, Wilkins SE, Kislinger T, Gygi SP, Schofield CJ, Dennis JW, Wouters BG, Neel BG.
  • Journal Title: Nat Cell Biol Volume: 18 Issue: 7 Pages: 803-813
  • DOI: 10.1038/ncb3376
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] RNF213 is associated with Intracranial Aneurysms in the French-Canadian population. (2016)
  • Author(s): Zhou S, Ambalavanan A, Rochefort D, Xie P, Bourassa CV, Hince P, Dionne-Laporte A, Spiegelman D, Gan-Or Z, Mirarchi C, Zaharieva V, Dupré N, Kobayashi H, Hitomi T, Harada K, Koizumi A, Xiong L, Dion PA, Rouleau GA.
  • Journal Title: Am J Hum Genet Volume: 99(5) Issue: 5 Pages: 1072-1085
  • DOI: 10.1016/j.ajhg.2016.09.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The importance of molecular diagnosis in the accurate diagnosis of systemic carnitine deficiency (2015)
  • Author(s): Hitomi T, Matsuura N, Shigematsu Y, Okano Y, Shinozaki E, Kawai M, Kobayashi H, Harada KH, Koizumi A.
  • Journal Title: Journal of Genetics Volume: 94（1） Issue: 1 Pages: 147-150
  • DOI: 10.1007/s12041-015-0486-0
  • Peer Reviewed
• [Journal Article] Genetic Study of Intracranial Aneurysms (2015)
  • Author(s): Yan JX, Hitomi T, Takenaka K, Kato M, Kobayashi H, Okuda H, Harada KH, Koizumi A.
  • Journal Title: Stroke Volume: 46(3) Issue: 3 Pages: 620-626
  • DOI: 10.1161/strokeaha.114.007286
  • Peer Reviewed
• [Journal Article] Biochemical and Functional Characterization of RNF213 (Mysterin) R4810K, a Susceptibility Mutation of Moyamoya Disease, in Angiogenesis In Vitro and In Vivo. (2015)
  • Author(s): Kobayashi H, Matsuda Y, Hitomi T, Okuda H, Shioi H, Matsuda T, Imai H, Sone M, Taura D, Harada KH, Habu T, Takagi Y, Miyamoto S, Koizumi A.
  • Journal Title: J Am Heart Assoc. Volume: 30;4(7) Issue: 7
  • DOI: 10.1161/jaha.115.002146
  • Peer Reviewed / Open Access
• [Presentation] 小児四肢疼痛発作症の遺伝疫学的検討 (2017)
  • Author(s): 加畑理咲子、小林果、奥田裕子、曹洋、人見敏明、原田浩二、小泉昭夫
  • Organizer: 第87回 日本衛生学会総会
  • Place of Presentation: フェニックス・シーガイア・リゾート（宮崎県宮崎市）
  • Year and Date: 2017-03-26
• [Presentation] やもや病感受性遺伝子mysterinのATPase機能喪失変異がangiogenesisに与える影響 (2016)
  • Author(s): 小林果、人見敏明、奥田裕子、塩井大智、原田浩二、小泉昭夫
  • Organizer: 第86回 日本衛生学会総会
  • Place of Presentation: 旭川市民文化会館(北海道旭川市）
  • Year and Date: 2016-05-11
• [Presentation] もやもや病感受性多型RNF213遺伝子p.R4810Kによるangiogenesis抑制のin vitroおよびin vivoでの検討 (2015)
  • Author(s): 松田佳子、小林果、人見敏明、奥田裕子、塩井大智、原田浩二、峰晴陽平、高木康志、宮本享、小泉昭夫
  • Organizer: 第27回日本脳循環代謝学会総会
  • Place of Presentation: 富山国際会議場（富山県富山市）
  • Year and Date: 2015-10-30
• [Presentation] Mysterin/RNF213 p.R4810K変異からみたもやもや病の特徴 (2015)
  • Author(s): 峰晴陽平、高木康志、森本貴昭、松田佳子、小林果、人見敏明、原田浩二、宮本享、小泉昭夫
  • Organizer: 第27回日本脳循環代謝学会総会
  • Place of Presentation: 富山国際会議場（富山県富山市）
  • Year and Date: 2015-10-30
• [Presentation] 内頸動脈管径とRNF213遺伝子多型によるもやもや病の診断 (2015)
  • Author(s): 森本貴昭、峰晴陽平、坂井信幸、高木康志、人見敏明、小林果、谷正一、上野泰、今村博敏、藤堂謙一、松田佳子、小泉昭夫、宮本享
  • Organizer: 第27回日本脳循環代謝学会総会
  • Place of Presentation: 富山国際会議場（富山県富山市）
  • Year and Date: 2015-10-30
• [Presentation] エクソーム解析を用いた脳動脈瘤患者の遺伝学的研究 (2015)
  • Author(s): 竹中 勝信、加藤雅康、野中裕康、人見敏明、厳俊霞、小林果、奥田裕子、原田浩二、小泉昭夫
  • Organizer: 第51回日本赤十字社医学会総会
  • Place of Presentation: 北見市民会館（北海道北見市）
  • Year and Date: 2015-10-15
• [Presentation] MysterinはIFNβによる抗血管形成シグナル経路のメディエーターとして働く (2015)
  • Author(s): 人見敏明、小林果、奥田裕子、曽根正勝、田浦大輔、原田浩二、土生敏行、小泉昭夫
  • Organizer: 第85回 日本衛生学会総会
  • Place of Presentation: アパローム紀の国
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] 血管内皮特異的mysterin変異体Tgマウスにおける低酸素による脳angiogenesis誘導の低下 (2015)
  • Author(s): 小林果、奥田裕子、塩井大智、松田佳子、人見敏明、原田浩二、小泉昭夫
  • Organizer: 第85回 日本衛生学会総会
  • Place of Presentation: アパローム紀の国
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] 血管平滑筋特異的mysterin変異体Tgマウスにおける低酸素誘導性肺arteriogenesisの抑制 (2015)
  • Author(s): 小林果、奥田裕子、塩井大智、松田佳子、人見敏明、原田浩二、小泉昭夫
  • Organizer: 第85回 日本衛生学会総会
  • Place of Presentation: アパローム紀の国
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] もやもや病感受性変異体は有糸分裂異常によりゲノム不安定性を誘導する (2014)
  • Author(s): 人見敏明、小林果、土生敏行、原田浩二、小泉昭夫
  • Organizer: 第84回 日本衛生学会総会
  • Place of Presentation: 岡山コンベンションセンター
  • Year and Date: 2014-05-25 – 2014-05-27
• [Presentation] もやもや病特異的iPS細胞由来血管内皮細胞における血管形成能の低下 (2014)
  • Author(s): 小林果、人見敏明、土生敏行、原田浩二、小泉昭夫
  • Organizer: 第84回 日本衛生学会総会
  • Place of Presentation: 岡山コンベンションセンター
  • Year and Date: 2014-05-25 – 2014-05-27
• [Remarks] 京都大学大学院医学研究科社会健康医学系専攻健康要因学講座環境衛生学分野
  • URL: http://130.54.180.142/index.htm
• [Remarks] 聖マリアンナ医科大学教員情報 医学部医学科環境保健人見敏明
  • URL: http://gyoseki.marianna-u.ac.jp/smuhp/KgApp?kyoinId=ymdsyoydggy
• [Remarks] 京都大学環境衛生学分野HP
  • URL: http://130.54.180.142/index.htm