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Development of a large-scale kinetic model of human organ systems

Research Project

Project/Area Number 19H04208
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 62010:Life, health and medical informatics-related
Research InstitutionKyushu Institute of Technology

Principal Investigator

Kurata Hiroyuki  九州工業大学, 大学院情報工学研究院, 教授 (90251371)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2021: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2019: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Keywordsシミュレーション / 全身代謝 / ロバストネス / 糖尿病 / コンピュータ / ダイナミクス / メカニズム / ダイナミックモデル / 創薬 / 動力学 / コンピュータシミュレーション / ヒト代謝 / 臓器 / 予測 / インスリン / 肝臓 / 数理モデリング / システム生物学 / 薬物動態学
Outline of Research at the Start

臨床実験や動物実験の一部を代替するために,世界で初めて,細胞内生体分子ネットワークと臓器間ネットワークを統合する分子,細胞,組織,臓器の階層的マルチスケール数理モデルを開発する.各臓器をつなげる血管内の物質動態を動力学方程式で記述し,各臓器細胞のゲノムスケール代謝システムをFlux Balance Analysis (FBA)で構築する.生理学や生化学実験データを基に代謝流束に制約条件を与えて,臓器特異的酵素活性分布(基質・生成物・蓄積物流束分布の全体)を推定する新規機械学習法を提案する.

Outline of Final Research Achievements

A virtual metabolic human model is a valuable complement to experimental biology and clinical studies, because in vivo research involves serious ethical and technical problems. I have proposed a multi-organ and multi-scale kinetic model that formulates the reactions of enzymes and transporters with the regulation of hormonal actions at postprandial and postabsorptive states. The computational model consists of 202 ordinary differential equations for metabolites with 217 reaction rates and 1141 kinetic parameter constants. It is the most comprehensive, largest and highly predictive model of the whole-body metabolism. The model predicted a glycerol kinase inhibitor to be an effective medicine for type 2 diabetes, which not only decreased hepatic triglyceride but also reduced plasma glucose. The model also enabled us to rationally design combination therapy.

Academic Significance and Societal Importance of the Research Achievements

臓器をひとつのコンパートメントと考える薬物動態モデルでは,臓器細胞内の分子メカニズムはブラックボックスである。本研究では,臓器間ネットワークと臓器を構成する細胞の生体分子ネットワークを統合するマルチスケール数理モデルを世界で初めて開発した。生体分子ネットワークの数理モデルを構築して,次世代の創薬CADを開発した。インスリン抵抗性の病態下で,糖尿病治療薬(構造的類似化合物で代謝酵素反応を阻害する薬剤)が引き起こす,多様な代謝応答をシミュレーションすることが可能となった。臨床実験の一部をコンピュータで代替するVirtual Physiological Human(VPH)の端緒を開いた。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (13 results)

All 2021 2020 2019 Other

All Int'l Joint Research (3 results) Journal Article (7 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 6 results,  Open Access: 4 results) Presentation (2 results) (of which Invited: 1 results) Remarks (1 results)

  • [Int'l Joint Research] Tulane university(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Ajou university(韓国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] VU University(オランダ)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] NeuroPred-FRL: An Interpretable Prediction Model for Identifying Neuropeptide using Feature Representation Learning2021

    • Author(s)
      Md Mehedi Hasan, Md Ashad Alam, Watshara Shoombuatong, Balachandran Manavalan, Hiroyuki Kurata
    • Journal Title

      Briefings in Bioinformatics

      Volume: NA Issue: 6

    • DOI

      10.1093/bib/bbab167

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Critical evaluation of web-based DNA N6-methyladenine site prediction tools2021

    • Author(s)
      Hasan Md Mehedi、Shoombuatong Watshara、Kurata Hiroyuki、Manavalan Balachandran
    • Journal Title

      Briefings in Functional Genomics

      Volume: 20 Issue: 4 Pages: 258-272

    • DOI

      10.1093/bfgp/elaa028

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Virtual metabolic human dynamic model for pathological analysis and therapy design for diabetes. iScience2021

    • Author(s)
      H. Kurata
    • Journal Title

      iScience

      Volume: 24 Issue: 2 Pages: 102101-102101

    • DOI

      10.1016/j.isci.2021.102101

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ヒト全身代謝システムの数理モデル2020

    • Author(s)
      倉田博之
    • Journal Title

      細胞

      Volume: 52 Pages: 376-379

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Computer-aided rational design of efficient NADPH production system by Escherichia coli pgi mutant using a mixture of glucose and xylose2020

    • Author(s)
      Yu Matsuoka, Hiroyuki Kurata.
    • Journal Title

      Front. Bioeng. Biotech.

      Volume: 8 Pages: 277-277

    • DOI

      10.3389/fbioe.2020.00277

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Self-replenishment cycles generate a threshold response2019

    • Author(s)
      Hiroyuki Kurata
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 17139-17139

    • DOI

      10.1038/s41598-019-53589-1

    • NAID

      120006773074

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ranking network mechanisms by how they fit diverse experiments and deciding on E. coli's ammonium transport and assimilation network2019

    • Author(s)
      Maeda Kazuhiro、Westerhoff Hans V.、Kurata Hiroyuki、Boogerd Fred C.
    • Journal Title

      npj Systems Biology and Applications

      Volume: 5 Issue: 1 Pages: 1-1

    • DOI

      10.1038/s41540-019-0091-6

    • NAID

      120006778226

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] ヒト全身代謝のコンピューターモデル開発と糖尿病治療への応用2021

    • Author(s)
      倉田博之
    • Organizer
      The future of diabetes 2021 online conference
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] ヒト全身代謝のコンピュータモデルの開発2020

    • Author(s)
      倉田博之,那須 拡生,吉森 瑠菜
    • Organizer
      化学工学会第51回秋季大会
    • Related Report
      2020 Annual Research Report
  • [Remarks] CADLIVE

    • URL

      http://www.cadlive.jp/

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report 2019 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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