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Molecular pathology of moyamoyta disease and its translational research toward prevention and drug development

Research Project

Project/Area Number 25253047
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Epidemiology and preventive medicine
Research InstitutionKyoto University

Principal Investigator

KOIZUMI Akio  京都大学, 医学(系)研究科(研究院), 教授 (50124574)

Co-Investigator(Kenkyū-buntansha) SONE Masakatsu  京都大学, 大学院医学研究科, 特定准教授 (40437207)
MIYAMOTO Susumu  京都大学, 大学院医学研究科, 教授 (70239440)
TAKAGI Yasushi  京都大学, 大学院医学研究科, 准教授 (40312227)
HABU Toshiyuki  武庫川女子大学, 生活環境学部, 准教授 (70346071)
YAMAZAKI Satoru  独立行政法人国立循環器病研究センター, 細胞生物学部, 室長 (70348796)
HARADA Koji  京都大学, 大学院医学研究科, 准教授 (80452340)
HITOMI Toshiaki  聖マリアンナ医科大学, 医学部, 准教授 (90405275)
Project Period (FY) 2013-10-21 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥43,940,000 (Direct Cost: ¥33,800,000、Indirect Cost: ¥10,140,000)
Fiscal Year 2015: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
Fiscal Year 2014: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
Fiscal Year 2013: ¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000)
Keywords分子遺伝疫学 / 予防医学 / 社会医学 / 衛生学 / 医歯薬学
Outline of Final Research Achievements

We found that RNF213 is the susceptibility gene for moyamoya disease (MMD and its R4810K variant is the founder mutation among Asians. In the present project、we expanded the research in three fields. First, we investigated association of R4810K with coronary artery disease (CAD), which is often complicated with MMD and found strong association between RNF213 R4810K and CAD. In the transgenic animal study, overexpression of R4757K in endothelial cells (human R4810K orthologue) was found to inhibit angiogenesis in brain under the hypoxia. Finally, we found that a small molecule which inhibits ATPase activity by interacting with A module is a promising candidate for drug development.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • Research Products

    (30 results)

All 2016 2015 2014 2013 Other

All Journal Article (14 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 12 results,  Open Access: 3 results) Presentation (13 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results) Remarks (3 results)

  • [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

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Early onset of moyamoya syndrome in a Down syndrome patient with the genetic variant RNF213 p.R4810K2015

    • Author(s)
      Pin Fee Chong, Reina Ogata, Hatasu Kobayashi, Akio Koizumi, Ryutaro Kira
    • Journal Title

      Brain Dev. Available

      Volume: Available online Issue: 8 Pages: 822-4

    • DOI

      10.1016/j.braindev.2014.12.006

    • Related Report
      2015 Annual Research Report 2014 Annual Research Report
    • 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

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The importance of molecular diagnosis in the accurate diagnosis of systemic carnitine deficiency2015

    • 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

    • Related Report
      2015 Annual Research Report 2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Genetic Study of Intracranial Aneurysms2015

    • 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

    • Related Report
      2015 Annual Research Report 2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] An Integrative Study of the Genetic, Social and Environmental Determinants of Chronic Kidney Disease Characterized by Tubulointerstitial Damages in the North Central Region of Sri Lanka2014

    • Author(s)
      Nanayakkara, S., Senevirathna, S., Abeysekera, T., Chandrajith, R., Ratnatunga, N., Gunarathne, E., Yan, J., Hitomi, T., Muso, E., Komiya, T., Harada, K., Liu, W., Kobayashi, H., Okuda, H., Sawatari, H., Matsuda, F., Yamada, R., Watanabe, T., Miyataka, H., Himeno, S., Koizumi, A.
    • Journal Title

      Journal of Occupational Health

      Volume: 56 Issue: 1 Pages: 28-38

    • DOI

      10.1539/joh.13-0172-OA

    • NAID

      130004848049

    • ISSN
      1341-9145, 1348-9585
    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 1. Pcf1, a large subunit of CAF-1, required for maintenance of checkpoint kinase Cds1 activity2014

    • Author(s)
      Kunoh T and Habu T.
    • Journal Title

      Springer Plus

      Volume: 3:30 Issue: 1 Pages: 1-8

    • DOI

      10.1186/2193-1801-3-30

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Genome-wide association study identifies no major founder variant in Caucasian moyamoya disease2013

    • Author(s)
      Liu W, Hitomi T, Kobayashi H, Koizumi A. et al.
    • Journal Title

      J Genet

      Volume: 92(3) Issue: 3 Pages: 605-609

    • DOI

      10.1007/s12041-013-0304-5

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Evaluation of intra-mitochondrial ATP levels identifies G0/G1 switch gene 2 as a positive regulator of oxidative phosphorylation2013

    • Author(s)
      Kioka H, Kato H, Fujikawa M, Tsukamoto O, Suzuki T, Imamura H, Nakano A, Higo S, Yamazaki S, Matsuzaki T, Tkafuji K, Asanuma H, Asakura M, Minamino T, Shintani Y, Yoshida M, Noji H, Kitakaze M, Komuro I, Asano Y and Takashima S
    • Journal Title

      PNAS

      Volume: 111 Issue: 1 Pages: 273-278

    • DOI

      10.1073/pnas.1318547111

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Rapid Progression of Unilateral Moyamoya Disease in a Patient with a Family History and an RNF213 Risk Variant2013

    • Author(s)
      Mineharu Y, Hitomi T, Kobayashi H Koizumi A. et al.
    • Journal Title

      Cerebrovasc Dis

      Volume: 36(2) Issue: 2 Pages: 155-7

    • DOI

      10.1159/000352065

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The moyamoya disease susceptibility variant RNF213 R4810K (rs112735431)2013

    • Author(s)
      Hitomi T, Habu T, Kobayashi H, Okuda H, Harada KH, Osafune K, Taura D, Sone M, Asaka I, Ameku T, Watanabe A, Kasahara T, Sudo T, Shiota F, Hashikata H, Takagi Y, Morito D, Miyamoto S, Nakao K, Koizumi A
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 439(4) Issue: 4 Pages: 419-426

    • DOI

      10.1016/j.bbrc.2013.08.067

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] p31comet inactivates the chemically induced Mad2-dependent spindle assembly checkpoint and leads to resistance to anti-mitotic drugs2013

    • Author(s)
      Habu T and Matsumoto T.
    • Journal Title

      Springer Plus

      Volume: 2:562 Issue: 1 Pages: 1-15

    • DOI

      10.1186/2193-1801-2-562

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] もやもや病の遺伝子変異2013

    • Author(s)
      小林果、人見敏明、小泉昭夫
    • Journal Title

      Clinical Neuroscience

      Volume: 31(12) Pages: 1147-1150

    • Related Report
      2013 Annual Research Report
  • [Journal Article] もやもや病感受性遺伝子mysterinにおける日中韓で共通な創始者多型と人類学的考察2013

    • Author(s)
      小泉昭夫、小林果
    • Journal Title

      DNA多型

      Volume: 21 Pages: 1-7

    • Related Report
      2013 Annual Research Report
  • [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
    • Year and Date
      2015-10-30
    • Related Report
      2015 Annual Research Report
  • [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
    • Year and Date
      2015-10-30
    • Related Report
      2015 Annual Research Report
  • [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
    • Year and Date
      2015-10-30
    • Related Report
      2015 Annual Research Report
  • [Presentation] In vitro and in vivo evidence on inhibition of angiogenesis by the Moyamoya susceptible gene and its mutation, RNF213 R4810K2015

    • Author(s)
      Koizumi A, Kobayashi H, Matsuda Y, Hitomi T, Okuda H, Shioi H, Matsuda T, Imai H, Sone M, Taura D, Harada KH, Takagi Y, Miyamoto S, Habu T.
    • Organizer
      4th International Moyamoya Meeting Berlin
    • Place of Presentation
      Berlin
    • Year and Date
      2015-07-02
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [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 日本衛生学会学術総会
    • Place of Presentation
      アバローム紀の国
    • Year and Date
      2015-03-26 – 2015-03-28
    • Related Report
      2014 Annual Research Report
  • [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 日本衛生学会学術総会
    • Place of Presentation
      アバローム紀の国
    • Year and Date
      2015-03-26 – 2015-03-28
    • Related Report
      2014 Annual Research Report
  • [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 日本衛生学会学術総会
    • Place of Presentation
      アバローム紀の国
    • Year and Date
      2015-03-26 – 2015-03-28
    • Related Report
      2014 Annual Research Report
  • [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 日本衛生学会学術総会
    • 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
    • Related Report
      2014 Annual Research Report
  • [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 日本衛生学会学術総会
    • 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
    • Related Report
      2014 Annual Research Report
  • [Presentation] Moyamoya 病のミニレビューと今後の研究の方向2014

    • Author(s)
      小泉昭夫、小林果、原田浩二、人見敏明
    • Organizer
      第13回 分子予防環境医学研究会
    • Place of Presentation
      和歌山県立文化会館
    • Related Report
      2013 Annual Research Report
  • [Presentation] Mysterin遺伝子のR4810K多型はもやもや病特異的iPS細胞由来血管内皮細胞においてSecurinの発現抑制を介して血管形成能を低下させる2014

    • Author(s)
      小林果、人見敏明、土生敏行、原田浩二、小泉昭夫
    • Organizer
      第13回 分子予防環境医学研究会
    • Place of Presentation
      和歌山県立文化会館
    • Related Report
      2013 Annual Research Report
  • [Presentation] もやもや病感受性変異体Mysterin R4810K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13回 分子予防環境医学研究会
    • Place of Presentation
      和歌山県立文化会館
    • Related Report
      2013 Annual Research Report
  • [Presentation] The E3 ligase Asb2 regulates cardiac development through targeting Smad9 for proteasomal degradation.2014

    • Author(s)
      Kyung-Duk Min
    • Organizer
      第78回日本循環器学会学術集会
    • Place of Presentation
      東京国際フォーラム
    • Related Report
      2013 Annual Research Report
  • [Remarks] 京都大学大学院医学研究科環境衛生学分野HP

    • URL

      http://hes.med.kyoto-u.ac.jp/

    • Related Report
      2015 Annual Research Report
  • [Remarks] 京都大学大学院医学研究科環境衛生学分野HP

    • URL

      http://hes.med.kyoto-u.ac.jp/

    • Related Report
      2014 Annual Research Report
  • [Remarks] 京都大学 大学院医学研究科 環境衛生学分野

    • URL

      http://130.54.180.142/index.html

    • Related Report
      2013 Annual Research Report

URL: 

Published: 2013-10-24   Modified: 2019-07-29  

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