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Development of newer animal model, biomarker, and treatment of depression by regulation of BDNFgene methylation using genome editing

Research Project

Project/Area Number 18K07575
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52030:Psychiatry-related
Research InstitutionKibi International University

Principal Investigator

Morinobu Shigeru  吉備国際大学, 保健医療福祉学部, 教授 (30191042)

Co-Investigator(Kenkyū-buntansha) 淵上 学  広島大学, 病院(医), 講師 (40403571)
田尻 直輝  名古屋市立大学, 医薬学総合研究院(医学), 准教授 (80782119)
津田 雅之  高知大学, 教育研究部医療学系基礎医学部門, 准教授 (90406182)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords脳由来神経栄養因子(BDNF) / うつ病 / DNA methylation / Tet1 / DNMT3a / BDNF / メチル化 / Dnmt3a / DNAメチル化 / Methylation / Genome editing / Dnmt / Depression
Outline of Final Research Achievements

It is known that the decreased expression of brain-derived neurotrophic factor (BDNF) in the hippocampus is associated with the pathophysiology of depression. To verify the involvement of the decreased cytosine methylation rates (CMRs) within the promoter of exon IV of the BDNF gene in the pathophysiology of depression, we developed the method of the artificial manipulation of the CMRs of the BDNF gene. Lentiviruses expressing the Fuw-dCas9-Tet1CD and Fuw-dCas9-Dnmt3a and guide RNA were produced by transfecting HEK239T cells with standard packaging vectors. After calculating the virus titer, the constructs with higher titer were transfected into the primary mouse cell culture to examine whether CMRs were altered by dCas9-Tet1 or dCas9-Dnmt3a. We found that while the dCas9-Tet1 fusion protein increased the levels of BDNF mRNA and BDNF protein with the decrease in the CMRs, the dCas9-Dnmt3a fusion protein decreased the levels of BDNF mRNA and BDNF protein with the increase in the CMRs.

Academic Significance and Societal Importance of the Research Achievements

うつ病動物モデルの脳およびうつ病患者の末梢血・脳由来DNAを対象としたBDNF遺伝子のシトシンのメチル化研究から、BDNF遺伝子exon IVのpromoter領域のメチル化率の低下が報告されている。しかしながらこれらのメチル化率の変化が、うつ病の原因として特異的な変化であるかは不明である。本研究の成果によってマウスを対象にBDNF遺伝子のメチル化を特異的に変動させる技術が開発された事になり、今後本実験で得られた手法をマウス脳に適用する事によって、うつ病の病態のエピジェネティクス領域からの一層の解明が進むと思われる。

Report

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

    (5 results)

All 2021 2020 2019 2018

All Journal Article (4 results) (of which Peer Reviewed: 4 results) Presentation (1 results)

  • [Journal Article] Chemogenetic activation of the mPFC alleviates impaired fear memory extinction in an animal model of PTSD2021

    • Author(s)
      Omura Jun、Fuchikami Manabu、Araki Motoaki、Miyagi Tatsuhiro、Okamoto Yasumasa、Morinobu Shigeru
    • Journal Title

      Progress in Neuro-Psychopharmacology and Biological Psychiatry

      Volume: 108 Pages: 110090-110090

    • DOI

      10.1016/j.pnpbp.2020.110090

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Alterations in DNA methylation rates of brain-derived neurotrophic factor in patients with schizophrenia2021

    • Author(s)
      Nojima S, Fuchikami M, Kataoka T, Araki M, Omura J, Miyagi T, Okamoto Y, Hishimoto A, Morinobu S
    • Journal Title

      The European Journal of Psychiatry

      Volume: 35 Issue: 2 Pages: 67-74

    • DOI

      10.1016/j.ejpsy.2020.08.003

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The role of glucocorticoid receptors in the induction and prevention of hippocampal abnormalities in an animal model of posttraumtic stress disorder2020

    • Author(s)
      Araki M, Fuchikami M, Omura J, Miyagi T, Nagashima N, Okamoto Y, Morinobu S
    • Journal Title

      Psychopharmacology

      Volume: in press Issue: 7 Pages: 2125-2137

    • DOI

      10.1007/s00213-020-05523-x

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Combined brain-derived neurotrophic factor with extinction training alleviate impaired fear extinction in an animal model of post-traumatic stress disorder.2018

    • Author(s)
      Kataoka T, Fuchikami M, Nojima S, Nagashima N, Araki M, Omura J, Miyagi T, Okamoto Y, Morinobu S
    • Journal Title

      Genes Brain & Behavior

      Volume: e12520 Issue: 7 Pages: 1-10

    • DOI

      10.1111/gbb.12520

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Presentation] 新たなうつ病の病態仮説<Imbalance of excitation-inhibition within the PFC>2019

    • Author(s)
      森信 繁、淵上 学
    • Organizer
      第38回躁うつ病の薬理・生化学的研究懇話会
    • Related Report
      2019 Research-status Report

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

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