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Identifing of common mechanisms of depression and cognitive decline associated with systemic diseases and application to treatment

Research Project

Project/Area Number 20H03577
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 52010:General internal medicine-related
Research InstitutionTottori University

Principal Investigator

NAKASO Kazuhiro  鳥取大学, 医学部, 教授 (30379648)

Co-Investigator(Kenkyū-buntansha) 岩田 正明  鳥取大学, 医学部, 教授 (40346367)
Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2023: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2022: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2021: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2020: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
KeywordsxCT / xc-系 / ミクログリア / グルタミン酸 / 認知症 / うつ症状 / アルツハイマー病 / パーキンソン病 / うつ / 認知機能障害 / うつ病 / 認知機能低下
Outline of Research at the Start

うつ症状・認知機能低下(以下 DCD : Depression and Cognitive Decline)は,脳・精神疾患に限らず,全身疾患に随伴して出現する“common disease的症状”である.従来より,認知症やうつ症状の病態に “細胞外グルタミン酸による興奮性神経毒性”の関与が知られておいる.本課題では,このグルタミン酸発生源として脳内ミクログリアに誘導されるシスチン・グルタミン酸交換系トランスポーター“ System xc- ”(xc-系)に注目し.DCD発現の共通メカニズムを明らかにする.さらに将来的な臨床応用を想定した,既存治療には無い特性を持つ新規治療の基盤確立を目指す.

Outline of Final Research Achievements

We investigated the mechanisms of common symptoms, such as cognitive impairment and depression, observed in various systemic and neurological disorders. We focused on the "system xc-/xCT" induced in brain microglia under pathological conditions and the extracellular glutamate released through it. We clarified its involvement in various pathological models. We observed a symptom-reducing effect of genetic deficiency of xCT or chemical xCT inhibitor on vitamin E deficiency (a type of oxidative stress, aging model), Alzheimer's disease model, and Parkinson's disease model. These results suggest that xCT could be a new therapeutic target for cognitive impairment and depression.

Academic Significance and Societal Importance of the Research Achievements

従来の認知機能障害やうつ症状の病態研究は,疾患ごとの原因に注目しつつ行われてきた.本研究では種々の疾患に共通な症状発現メカニズムの候補として「xc-系/xCT由来のグルタミン酸」に注目し,新規治療標的分子として位置付けた.さらに,この標的分子を制御できる化合物や抗体を得ることができれば,「認知希望障害やうつ症状克服」という社会的ニーズに応えることが可能となる.これは将来的には神経・精神疾患だけでなく,多種多様な疾患に随伴して見られる認知希望障害やうつ症状対策への波及効果が期待出来る.

Report

(4 results)
  • 2023 Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (6 results)

All 2023 2022 2020

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 2 results) Presentation (3 results) (of which Invited: 1 results)

  • [Journal Article] TYRO3 promotes chemoresistance via increased LC3 expression in pancreatic cancer2023

    • Author(s)
      Kazushi Hara, Yosuke Horikoshi, Masaki Morimoto, Kazuhiro Nakaso, Teppei Sunaguchi, Tatsuyuki Kurashiki, Yuji Nakayama, Takehiko Hanaki, Manabu Yamamoto, Teruhisa Sakamoto, Yoshiyuki Fujiwara, Tatsuya Matsura.
    • Journal Title

      Translational Oncology

      Volume: 28 Pages: 101608-101608

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Molecular mechanisms underlying the promotion of wound repair by coenzyme Q10: PI3K/Akt signal activation via alterations to cell membrane domains2022

    • Author(s)
      Tatsuyuki Kurashiki, Yosuke Horikoshi, Koki Kamizaki, Teppei Sunaguchi, Kazushi Hara, Masaki Morimoto, Yoshinori Kitagawa, Kazuhiro Nakaso, Akihiro Otsuki, Tatsuya Matsura
    • Journal Title

      Journal of Clinical Biochemistry and Nutrition

      Volume: 70 Issue: 3 Pages: 222-230

    • DOI

      10.3164/jcbn.21-141

    • NAID

      130008140083

    • ISSN
      0912-0009, 1880-5086
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Molecular mechanisms underlying the promotion of wound repair by coenzyme Q10: PI3K/Akt signal activation via alterations to cell membrane domains2022

    • Author(s)
      Tatsuyuki Kurashiki, Yosuke Horikoshi, Kouki Kamizaki, Teppei Sunaguchi, Kazushi Hara, Masaki Morimoto, Yoshinori Kitagawa, Kazuhiro Nakaso, Akihiro Otsuki and Tatsuya Matsura
    • Journal Title

      J Clin Biochem Nutr

      Volume: -

    • NAID

      130008140083

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Presentation] ビタミンE欠乏マウスの精神神経症状におけるミクログリアxCTの関与2023

    • Author(s)
      長嶺秀俊,堀越洋輔,中曽一裕
    • Organizer
      第32回ビタミンE研究会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 認知症治療標的候補としてのミクログリアxCT2023

    • Author(s)
      中曽一裕
    • Organizer
      Tottori Basic Research Forum
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] MPTP誘発パーキンソン病モデルにおける活動性低下は ミクログリアxCT/xc- 系と関係している2020

    • Author(s)
      中曽一裕,大端周,北川良憲,堀越洋輔,倉敷達之,松浦達也
    • Organizer
      第73回日本酸化ストレス学会・第20回日本NO学会合同学術集会
    • Related Report
      2020 Annual Research Report

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Published: 2020-04-28   Modified: 2025-01-30  

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