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A study on abnormal cerebrovascular function and accelerated inflammation in the developing brain with Down syndrome

Research Project

Project/Area Number 18K06940
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionKyoto Pharmaceutical University

Principal Investigator

Ishihara Keiichi  京都薬科大学, 薬学部, 准教授 (80340446)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywordsダウン症候群 / 神経新生 / 網羅的遺伝子発現解析 / 炎症 / 脳マクロファージ / 炎症細胞 / 脳発達 / 血管 / モデルマウス / 血管形成 / ミクログリア / ダウン症 / 発達遅滞
Outline of Final Research Achievements

Down syndrome (DS), is the most common genetic cause of intellectual disability that is assumed to be associated with delayed brain development. The aim of this research project is to understand the mechanisms underlying the delayed brain development in DS. For this purpose, a comprehensive expression analysis of genes was employed. DNA microarray analysis revealed that inflammation-related genes are increased in expression, and flowcytometric analysis revealed that increased expression of inflammation-related genes is caused by increased number of inflammatory cells. Furthermore, we demonstrated that triplication of the Erg gene resulted in increased number of inflammatory cells. Separately, we also identified a decreased expression of Tbx1 gene, which related to brain angiogenesis, in the brain of DS mouse models. Although we failed to detect an abnormal brain-vasculature in DS embryos, we proposed that Erg and Tbx1 genes are assumed to play a role in DS intellectual disability.

Academic Significance and Societal Importance of the Research Achievements

ダウン症の知的障害の原因などは全く分かっていなかったが、我々は、新しくダウン症の脳発達の遅れや知的障害に関係していると思われる遺伝子としてErg遺伝子とTbx1遺伝子を発見した。特に、Erg遺伝子では、胎児期の脳発達の遅れの原因とされる神経新生の低下の原因であることもマウスを用いた実験で明らかにしたことは、ダウン症の知的障害の胎内治療の実現化において重要な知見であると考えている。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (19 results)

All 2021 2020 2019 2018 Other

All Int'l Joint Research (2 results) Journal Article (6 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Open Access: 3 results) Presentation (8 results) (of which Int'l Joint Research: 1 results,  Invited: 6 results) Remarks (3 results)

  • [Int'l Joint Research] WEHI/University of Melbourne(オーストラリア)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] A*STAR(シンガポール)

    • Related Report
      2018 Research-status Report
  • [Journal Article] Is Neuron-Vascular Communication Disturbed in the Delayed Prenatal Brain Development of a Mouse Model of Down Syndrome?2021

    • Author(s)
      Ishihara Keiichi
    • Journal Title

      YAKUGAKU ZASSHI

      Volume: 141 Issue: 3 Pages: 369-373

    • DOI

      10.1248/yakushi.20-00198-5

    • NAID

      130007992978

    • ISSN
      0031-6903, 1347-5231
    • Year and Date
      2021-03-01
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Brain Development Coordinated by Interactions between Neurons, Glial Cells and Central Vascular System, and Disease Caused by Its Disturbance2021

    • Author(s)
      石原慶一、水谷 健一
    • Journal Title

      YAKUGAKU ZASSHI

      Volume: 141 Issue: 3 Pages: 333-334

    • DOI

      10.1248/yakushi.20-00198-F

    • NAID

      130007992977

    • ISSN
      0031-6903, 1347-5231
    • Year and Date
      2021-03-01
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Decrease in the T-box1 gene expression in embryonic brain and adult hippocampus of Down syndrome mouse models.2021

    • Author(s)
      Shimizu R, Ishihara K, Kawashita E, Sago H, Yamakawa K, Mizutani K, & Akiba S.
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 535 Pages: 87-92

    • DOI

      10.1016/j.bbrc.2020.12.026

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Perturbation of the immune cells and prenatal neurogenesis by the triplication of the Erg gene in mouse models of Down syndrome.2020

    • Author(s)
      Ishihara K, Shimizu R, Takata K, Kawashita E, Amano K, Shimohata A, Low D, Nabe T, Sago H, Alexander WS, Ginhoux F, Yamakawa K, Akiba S.
    • Journal Title

      Brain Pathology

      Volume: 30 Issue: 1 Pages: 75-91

    • DOI

      10.1111/bpa.12758

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Copper accumulation in the brain of Down syndrome model mice and its pathophysiological significance2019

    • Author(s)
      石原慶一,河下映里,秋葉 聡
    • Journal Title

      Folia Pharmacologica Japonica

      Volume: 154 Issue: 6 Pages: 335-339

    • DOI

      10.1254/fpj.154.335

    • NAID

      130007754367

    • ISSN
      0015-5691, 1347-8397
    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Copper accumulation in the brain causes the elevation of oxidative stress and less anxious behavior in Ts1Cje mice, a model of Down syndrome.2019

    • Author(s)
      Ishihara K, Kawashita E, Shimizu R, Nagasawa K, Yasui H, Sago H, Yamakawa K, Akiba S.
    • Journal Title

      Free Radic Biol Med.

      Volume: 134 Pages: 248-259

    • DOI

      10.1016/j.freeradbiomed.2019.01.015

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] ダウン症モデルマウスと病態研究について2020

    • Author(s)
      石原慶一
    • Organizer
      第2回日本ダウン症学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] ダウン症の胎生期脳発達遅滞における神経-血管相互作用異常の可能性2020

    • Author(s)
      石原慶一
    • Organizer
      日本薬学会第140年会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] ダウン症モデルマウス成体脳での銅蓄積~新規治療標的としての可能性~2020

    • Author(s)
      石原慶一
    • Organizer
      日本薬学会第140年会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Comparative elementomic analysis reveals copper accumulation in the brain in Ts1Cje, a mouse model of Down syndrome2019

    • Author(s)
      Keiichi Ishihara, Eri Kawashita, Ryohei Shimizu, Hiroyuki Yasui, Kazuki Nagasawa, Haruhiko Sago, Kazuhiro Yamakawa, Satoshi Akiba
    • Organizer
      3rd International Conference of the Trisomy 21 Research Society
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] ダウン症中枢症状の治療標的候補としての銅蓄積の同定2019

    • Author(s)
      石原慶一
    • Organizer
      第30回日本微量元素学会学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] ダウン症モデルマウスにおける血管新生調節転写因子の3コピー化による胎生期ニューロン新生異常.2019

    • Author(s)
      石原慶一
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Elementomics reveals the accumulation of copper in the brain of a Down syndrome model mouse and its pathophysiological significance.2019

    • Author(s)
      Keiichi Ishihara
    • Organizer
      The 92nd Annual Meeting of the Japanese Pharmacological Society
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] ダウン症モデルマウスにおける炎症性細胞数異常および大脳皮質発達遅延とその原因遺伝子の同定.2018

    • Author(s)
      石原慶一、清水涼平、河下映里、ウォレン アレキサンダー、左合治彦、山川和弘、秋葉 聡
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Remarks] 京都薬科大学 病態生化学分野

    • URL

      https://labo.kyoto-phu.ac.jp/byoutai/byoutai-j.html

    • Related Report
      2020 Annual Research Report
  • [Remarks] 京都薬科大学 病態生化学分野

    • URL

      http://labo.kyoto-phu.ac.jp/byoutai/byoutai-j.html

    • Related Report
      2019 Research-status Report
  • [Remarks] 京都薬科大学病態生化学分野

    • URL

      http://labo.kyoto-phu.ac.jp/byoutai/achievement.html

    • Related Report
      2018 Research-status Report

URL: 

Published: 2018-04-23   Modified: 2022-01-27  

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