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Role of Reelin/Ephrin pathway for improvement of cognitive function of dementia animals by cell transplantation remedy

Research Project

Project/Area Number 21K07529
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52030:Psychiatry-related
Research InstitutionSt. Marianna University School of Medicine

Principal Investigator

Takai Kenji  聖マリアンナ医科大学, 医学部, 教授 (60121167)

Co-Investigator(Kenkyū-buntansha) 清水 潤  聖マリアンナ医科大学, 医学部, 教授 (30509964)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2023: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2022: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Keywords認知症 / hiPS由来神経前駆細胞 / 細胞移植 / Reelin / Eph/ephrin経路 / Reelin分泌細胞 / 海馬治療 / 神経再生 / Eph/Ephrin経路 / iPS細胞 / 神経細胞分化 / 神経細胞移植治療 / リーリン/エフリン経路
Outline of Research at the Start

我々は認知症モデルマウスにヒトiPS(hiPS)細胞由来の(NSP)神経幹・前駆細胞を移植して認知機能回復を認めた。移植は神経回路を再構築している可能性が高い。移植NSP細胞のReelin産生、その宿主と移植細胞への作用、下流のDab1とAktのリン酸化、EphrinB3へのシナプス形成促進、が推定される。EphA4のシグナル伝達は遮断され海馬シナプスの機能障害は改善されると考えられ、海馬での神経再生により神経回路が再構築され、認知機能が改善されると考えられる。移植NSP細胞が認知症での解剖学的・機能的な再生を起こす際の神経回路再構築及び、宿主神経組織との高次構造形成時の回復機構を解明する。

Outline of Final Research Achievements

Hippocampal neural regeneration and Reelin signaling are important for improving cognitive function. Treatment will be performed by transplanting human iPS-derived NSPC (neural stem/progenitor cells), and we explored how Reelin and downstream signaling work. We will investigate the intracellular signaling downstream of Reelin before and after transplantation to explore the mechanism of NSPC fate determination, colonization, and neural circuit formation in recovery. It was likely that NSPC transplantation will reconstruct the neural circuitry of dementia mice. In this process, NSPC produce Reelin, which acts on the host and transplanted cells to phosphorylate downstream Dab1 and Akt, and through downstream intracellular signaling, EphrinB3 activates synapse formation.

Academic Significance and Societal Importance of the Research Achievements

アルツハイマー型認知症の治療薬として新薬が相次いで承認された。中核症状の治療薬として、塩酸ドネペジルに加えて、同じくアセチルコリンエステラーゼ阻害薬(AChEI)であるガランタミン、リバスチグミンが承認され、さらにN-methyl-D-aspartate(NMDA)受容体拮抗薬であるメマンチンも承認された。いずれも効能・効果は「進行抑制」である。しかし、実際には「進行抑制」だけではない様々な効果を認める。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (10 results)

All 2023 2022 2021

All Journal Article (9 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 9 results,  Open Access: 8 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Chemokines and chemokine receptors as promising targets in rheumatoid arthritis2023

    • Author(s)
      Murayama Masanori A.、Shimizu Jun、Miyabe Chie、Yudo Kazuo、Miyabe Yoshishige
    • Journal Title

      Frontiers in Immunology

      Volume: 14 Pages: 1100869-1100869

    • DOI

      10.3389/fimmu.2023.1100869

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Innate immune responses in Beh?et disease and relapsing polychondritis2023

    • Author(s)
      Shimizu Jun、Murayama Masanori A.、Mizukami Yoshihisa、Arimitsu Nagisa、Takai Kenji、Miyabe Yoshishige
    • Journal Title

      Frontiers in Medicine

      Volume: 10 Pages: 1055753-1055753

    • DOI

      10.3389/fmed.2023.1055753

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nationwide cross-sectional survey of patients with relapsing polychondritis in 2019 demonstrates reduction of airway involvement compared with that in 2009.2022

    • Author(s)
      Shimizu J, Yamano Y, Kawahara K, Suzuki N.
    • Journal Title

      Sci Rep

      Volume: 12(1) Issue: 1 Pages: 465-465

    • DOI

      10.1038/s41598-021-04493-0

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mechanical model of steady-state and inflammatory conditions in patients with relapsing polychondritis: A review.2022

    • Author(s)
      Shimizu J, Suzuki N.
    • Journal Title

      Medicine

      Volume: 101 Issue: 8 Pages: e28852-e28852

    • DOI

      10.1097/md.0000000000028852

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Immunopathology of Behcet’s Disease: An Overview of the Metagenomic Approaches2022

    • Author(s)
      Shimizu Jun、Murayama Masanori A.、Miyabe Yoshishige、Suzuki Noboru
    • Journal Title

      Rheumato

      Volume: 2 Issue: 3 Pages: 74-86

    • DOI

      10.3390/rheumato2030010

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Nicotine treatment regulates PD-L1 and PD-L2 expression via inhibition of Akt pathway in HER2-type breast cancer cells2022

    • Author(s)
      Murayama Masanori A.、Takada Erika、Takai Kenji、Arimitsu Nagisa、Shimizu Jun、Suzuki Tomoko、Suzuki Noboru
    • Journal Title

      PLOS ONE

      Volume: 17 Issue: 1 Pages: e0260838-e0260838

    • DOI

      10.1371/journal.pone.0260838

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Dementia model mice exhibited improvements of neuropsychiatric symptoms as well as cognitive dysfunction with neural cell transplantation2021

    • Author(s)
      Murayama Masanori A.、Arimitsu Nagisa、Shimizu Jun、Fujiwara Naruyoshi、Takai Kenji、Okada Yoko、Hirotsu Chieko、Takada Erika、Suzuki Tomoko、Suzuki Noboru
    • Journal Title

      Experimental Animals

      Volume: 70 Issue: 3 Pages: 387-397

    • DOI

      10.1538/expanim.21-0008

    • NAID

      130008072160

    • ISSN
      0007-5124, 1341-1357, 1881-7122
    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Female dominance of both spatial cognitive dysfunction and neuropsychiatric symptoms in a mouse model of Alzheimer’s disease2021

    • Author(s)
      Murayama Masanori A.、Arimitsu Nagisa、Shimizu Jun、Fujiwara Naruyoshi、Takai Kenji、Ikeda Yoshiki、Okada Yoko、Hirotsu Chieko、Takada Erika、Suzuki Tomoko、Suzuki Noboru
    • Journal Title

      Experimental Animals

      Volume: 70 Issue: 3 Pages: 398-405

    • DOI

      10.1538/expanim.21-0009

    • NAID

      130008072161

    • ISSN
      0007-5124, 1341-1357, 1881-7122
    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Defective Reelin/Dab1 signaling pathways associated with disturbed hippocampus development of homozygous yotari mice.2021

    • Author(s)
      Arimitsu N, Mizukami Y, Shimizu J, Takai K, Suzuki T, Suzuki N
    • Journal Title

      Molecular and Cellular Neuroscience

      Volume: 112 Pages: 103614-103614

    • DOI

      10.1016/j.mcn.2021.103614

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Presentation] Gut Microbe Metabolite Short-Chain Fatty Acids May Associate with Development of Respiratory Involvement in Patients with Relapsing Polychondritis2022

    • Author(s)
      Shimizu J
    • Organizer
      ACR Convergence 2022
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research

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Published: 2021-04-28   Modified: 2025-01-30  

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