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The innovative drug development that targeted molecules associated with coronary artery diseases and its functional analysis

Research Project

Project/Area Number 16H04726
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical genome science
Research InstitutionNational Center for Geriatrics and Gerontology

Principal Investigator

OZAKI Kouichi  国立研究開発法人国立長寿医療研究センター, メディカルゲノムセンター, 部長 (50373288)

Co-Investigator(Kenkyū-buntansha) 伊藤 薫  国立研究開発法人理化学研究所, 生命医科学研究センター, チームリーダー (50375664)
Research Collaborator YOSHII Mayumi  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥16,380,000 (Direct Cost: ¥12,600,000、Indirect Cost: ¥3,780,000)
Fiscal Year 2018: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2017: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2016: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Keywords虚血性心疾患 / 動脈硬化 / 創薬 / 虚血性心疾患感受性分子 / 低分子化合物 / 虚血性心疾患感受性分子群 / 分子機能 / 結合阻害低分子化合物 / BRAP / NFKBIB / 結合抑制低分子 / FURIN / LDLR / ELISA系 / 感受性分子
Outline of Final Research Achievements

We have performed the discovery of low-molecular weight compound (LMWC) which interfere the interaction and function of BRAP, associated most strongly with coronary artery diseases (CAD) susceptibility in Japanese, and IkB-beta a mediator of inflammation. We developed ELISA system for BRAP-IkB-beta interaction and performed interfere experiments for the binding by 9,600 low molecular weight compounds as well as selected its structural analogs. Finally, we have obtained 9 LMWCs that strongly interfered the BRAP-IkB-beta binding inwhich 3 molecules inhibited more than 40% of the proliferation of human artery smooth muscle cells. We also selected FURIN associated with CAD as another target for drug development. FURIN is a molecule with structural similarity of PCSK9, and interacts with LDL receptor. We have also developed ELISA system for FURIN-LDLR binding and have implemented LMWC screening that interfered the interaction using libraries consist of 9,600 and 22,400 molecules so far.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は遺伝学、分子生物学的手法により発見したCADの真の感受性分子をターゲットとした創薬に関連しており、これまでに無い革新的かつ先端的な点が学術的意義として挙げられる。また、CADは日本を含む世界における死因が上位である疾患の一つであることからその新たな予防法、革新的な治療法に繋がる成果の開発は社会的意義がある。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (20 results)

All 2019 2018 2017 2016

All Journal Article (10 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 10 results,  Open Access: 7 results) Presentation (6 results) (of which Int'l Joint Research: 6 results,  Invited: 1 results) Book (4 results)

  • [Journal Article] Risk prediction models for dementia constructed by supervised principal component analysis using miRNA expression data2019

    • Author(s)
      Shigemizu D, Akiyama S, Asanomi Y, Boroevich KA, Sharma A, Tsunoda T, Matsukuma K, Ichikawa M, Sudo H, Takizawa S, Sakurai T, Ozaki K, Ochiya T, Niida S.
    • Journal Title

      Communication Biology

      Volume: 2 Issue: 1 Pages: 77-77

    • DOI

      10.1038/s42003-019-0324-7

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure.2018

    • Author(s)
      Nomura S, Satoh M, Fujita T, Higo T, Sumida T, Ko T, Yamaguchi T, Tobita T, Naito AT, Ito M, Fujita K, Harada M, Toko H, Kobayashi Y, Ito K, Takimoto E, Akazawa H, Morita H, Aburatani H, Komuro I.
    • Journal Title

      Nat Commun.

      Volume: 9 Issue: 1 Pages: 4435-4435

    • DOI

      10.1038/s41467-018-06639-7

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Blood lipid-related low-frequency variants in LDLR and PCSK9 are associated with onset age and risk of myocardial infarction in Japanese.2018

    • Author(s)
      2)Tajima T, Morita H, Ito K, Yamazaki T, Kubo M, Komuro I, Momozawa Y.
    • Journal Title

      Scientific Reports

      Volume: 8 (1) Issue: 1 Pages: 8107-8107

    • DOI

      10.1038/s41598-018-26453-x

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] IMSindel: An accurate intermediate-size indel detection tool incorporating de novo assembly and gapped global-local alignment with split read analysis2018

    • Author(s)
      Shigemizu Daichi、Miya Fuyuki、Akiyama Shintaro、Okuda Shujiro、Boroevich Keith A、Fujimoto Akihiro、Nakagawa Hidewaki、Ozaki Kouichi、Niida Shumpei、Kanemura Yonehiro、Okamoto Nobuhiko、Saitoh Shinji、Kato Mitsuhiro、Yamasaki Mami、Matsunaga Tatsuo、Mutai Hideki、Kosaki Kenjiro、Tsunoda Tatsuhiko
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 5608-5608

    • DOI

      10.1038/s41598-018-23978-z

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Comparative analysis of cerebrospinal fluid metabolites in Alzheimer’s disease and idiopathic normal pressure hydrocephalus in a Japanese cohort.2018

    • Author(s)
      1)Nagata Y, Hirayama A, Ikeda S, Shirahata A, Shoji F, Maruyama M, Kayano M, Bundo M, Hattori K, Yoshida S, Goto Y, Urakami K, Soga T, Ozaki K and Niida S.
    • Journal Title

      Biomarker Research

      Volume: 6 Issue: 1 Pages: 1-11

    • DOI

      10.1186/s40364-018-0119-x

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Molecular genetics of coronary artery disease2017

    • Author(s)
      Ozaki K
    • Journal Title

      eLS (Encyclopedia of Life Sciences)

      Volume: November Pages: 1-10

    • DOI

      10.1002/9780470015902.a0027329

    • NAID

      40021386936

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mutations in NOD2 cause aggressive periodontitis.2017

    • Author(s)
      2)Sudo T, Okada Y, Ozaki K, Urayama K, Kanai M, Kobayashi H, Gokyu M, Izumi Y, Tanaka T.
    • Journal Title

      Journal of Dental Research

      Volume: 96 Issue: 10 Pages: 1100-1105

    • DOI

      10.1177/0022034517715432

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of six novel genetic loci associated with atrial fibrillation in Japanese population.2017

    • Author(s)
      Low SK, Takahashi A, Ebana Y, Ozaki K, Christophersen IE, Ellinor PT, AFGen Consortium, Ogishima S, Yamamoto M, Satoh M, Sasaki M, Yamaji T, Iwasaki M, Tsugane S, Tanaka K, Naito M, Wakai K, Tanaka H, Furukawa T, Kubo M, Ito K, Kamatani Y, Tanaka T.
    • Journal Title

      Nature Genetics

      Volume: - Issue: 6 Pages: 953-958

    • DOI

      10.1038/ng.3842

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Clinical utility and functional analysis of variants in atrial fibrillation-associated locus 4q25.2017

    • Author(s)
      Ebana Y, Ozaki K, Liu L, Hachiya H, Hirao K, Isobe M, Kubo M, Tanaka T, Furukawa T.
    • Journal Title

      Journal of Cardiology

      Volume: - Issue: 4 Pages: 366-373

    • DOI

      10.1016/j.jjcc.2016.11.016

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A functional SNP in FLT1 increases risk of coronary artery disease in a Japanese population.2016

    • Author(s)
      Konta A, Ozaki K, Sakata Y, Takahashi A, Morizono T, Suna S, Onouchi Y, Tsunoda T, Kubo M, Komuro I, Eishi Y, Tanaka T.
    • Journal Title

      Journal of Human Genetics

      Volume: 61 Issue: 5 Pages: 435-441

    • DOI

      10.1038/jhg.2015.171

    • NAID

      40020825254

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Presentation] Trans-ethnic meta-analysis of genome-wide association studies for coronary artery disease reveals genetic differences between Japanese and Europeans2018

    • Author(s)
      Matsunaga H, Koyama K, Onouchi Y, Ozaki K, Morita H, Akazawa H, Komuro I, Akiyama M, Kubo M, Kamatani Y, Ito K.
    • Organizer
      ASHG 2018 Annual Meeting (USA)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Trans-Ethnic Meta-Analysis of Genome-Wide Association Studies for Coronary Artery Disease Highlights the Importance of Immune System2018

    • Author(s)
      Matsunaga H, Ito K, Akiyama M, Koyama S, Onouchi Y, Ozaki K, Morita H, Akazawa H, Kamatani Y, Ko,uro I.
    • Organizer
      American Heart Association SCIENTIFIC SESSION 2018 (USA)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 14.The construction of risk prediction models for dementia with supervised principal component analysis using miRNA expression data2018

    • Author(s)
      Shigemizu D, Akiyama S, Asanomi Y, Boroevich KA, Sharma A, Tsunoda T, Matsukuma K, Ichikawa M, Sudo H, Takizawa S, Sakurai T, Ozaki K, Niida S.
    • Organizer
      The American Society of Human Genetics 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 16.Genetic analysis for late-onset Alzheimer's disease in Japanese population2018

    • Author(s)
      Ozaki K
    • Organizer
      Asian Forum on Alzheimer’s and Dementia 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Biological and pharmaceutical investigation for molecules associated with coronary artery disease2018

    • Author(s)
      Ozaki K
    • Organizer
      Genomic Medicine 2018
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Up-regulation of FLT1 by a novel functional SNP increases risk of coronary artery disease through an inflammatory activation.2016

    • Author(s)
      Ozaki K, Konta A, Tanaka T.
    • Organizer
      13th International Congress of Human Genetics (ICHG2016)
    • Place of Presentation
      京都市
    • Year and Date
      2016-04-06
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Book] 認知症の最新医療;メディカルゲノムと認知症2019

    • Author(s)
      尾崎浩一
    • Total Pages
      6
    • Publisher
      フジメディカル出版
    • Related Report
      2018 Annual Research Report
  • [Book] 虚血性心疾患の遺伝的背景とプレシジョン・メディシン2018

    • Author(s)
      尾崎浩一、田中敏博
    • Total Pages
      9
    • Publisher
      医学のあゆみ
    • Related Report
      2018 Annual Research Report
  • [Book] プレシジョンメディシン ~ビッグデータの構築・分析から臨床応用・課題まで~ 第4章;血性心疾患感受性遺伝子とプレシジョンメディシン2018

    • Author(s)
      尾崎浩一
    • Total Pages
      7
    • Publisher
      NTS inc.
    • Related Report
      2018 Annual Research Report
  • [Book] アンチ・エイジング医学;虚血性心疾患の分子遺伝学2017

    • Author(s)
      尾崎浩一
    • Total Pages
      9
    • Publisher
      メディカルレビュー社
    • ISBN
      9784779219771
    • Related Report
      2017 Annual Research Report

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Published: 2016-04-21   Modified: 2020-03-30  

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