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Comprehensive study of "molecular-controlled cell death and autophagy" in dementia and cerebrovascular disease in the elderly

Research Project

Project/Area Number 18K07426
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52010:General internal medicine-related
Research InstitutionTokyo Medical University

Principal Investigator

TAKAHIKO UMAHARA  東京医科大学, 医学部, 客員教授 (70266477)

Co-Investigator(Kenkyū-buntansha) 秋元 治朗  東京医科大学, 医学部, 教授 (10212440)
羽生 春夫  東京医科大学, 医学部, 特任教授 (10228520)
清水 聰一郎  東京医科大学, 医学部, 主任教授 (10385031)
平尾 健太郎  東京医科大学, 医学部, 講師 (40516639)
河野 道宏  東京医科大学, 医学部, 主任教授 (50718707)
橋本 孝朗  東京医科大学, 医学部, 准教授 (60266517)
Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2021: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000)
Fiscal Year 2020: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000)
Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords血管性認知症 / 脳血管障害 / 頚動脈プラ-ク / オ-トファジ- / Beclin1 / 14-3-3蛋白 / HMGB1 / リン酸化TDP-43 / オートファジ- / Rubicon / beclin1 / BRCA1 / 脳動脈硬化 / 頸動脈プラ-ク / オートファーゴソーム / TDP-43 / Beclin-1 / 14-3-3タンパク / マクロファ-ジ / 動脈硬化 / 内頚動脈プラ-ク / 分子制御された細胞死 / 認知症 / 分子制御細胞死 / TDP-43
Outline of Final Research Achievements

Dementia and cerebrovascular accidents are the two major neurological disorders of the elderly. The true pathological condition is nerve cell death, and "autophagy" is also involved. Autophagy is the action by which cells decompose and reuse unnecessary proteins in themselves. When 14-3-3 protein binds to Beclin1, autophagy is suppressed and activated by binding to HMGB1. We confirmed the new finding, Beclin1 localization in human carotid plaque / cerebral arteriosclerotic lesions, and confirmed co-localization with 14-3-3 protein and HMGB1. Beclin1 control may be involved in autophagy control.
Localization of TDP-43, the causative protein of frontotemporal dementia, in internal carotid artery plaque, cerebral arteriosclerosis, and chronic cerebral infarction, 14-3-3 protein, co-localization with HMGB1 confirmed.

Academic Significance and Societal Importance of the Research Achievements

認知症と脳血管障害は高齢者の2大神経疾患である。認知症の真の病態は大脳皮質神経細胞死で、脳梗塞では虚血性神経細胞死である。よって両疾患の本質的治療ターゲットは神経細胞死抑制である。最近「オ-トファジ-」の神経細胞死への関与が指摘された。Beclin-1に14-3-3蛋白が結合するとオ-トファジ-は抑制され、HMGB1との結合で活性化する。3物質の共局在の知見はこれまでにないが今回確認した。Beclin1の制御はオートファジ-制御に寄与しうる。
前頭側頭型認知症の原因蛋白のひとつであるの脳動脈硬化巣と慢性期脳梗塞での局在を確認した。これは血管性認知症の治療法開発に寄与する

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (3 results)

All 2020

All Journal Article (3 results) (of which Peer Reviewed: 3 results)

  • [Journal Article] Essential autophagic protein Beclin 1 localizes to atherosclerotic lesions of human carotid and major intracranial arteries2020

    • Author(s)
      Umahara Takahiko、Uchihara Toshiki、Hirao Kentaro、Shimizu Soichiro、Hashimoto Takao、Kohno Michihiro、Hanyu Haruo
    • Journal Title

      Journal of the Neurological Sciences

      Volume: 414 Pages: 116836-116836

    • DOI

      10.1016/j.jns.2020.116836

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Phosphorylated TDP-43 localizes to chronic cerebral infarctions in human brains.2020

    • Author(s)
      Umahara T, Uchihara T, Hirao K, Shimizu S, Hanyu H.
    • Journal Title

      Histology and Histopathology

      Volume: 35 Pages: 1023-1028

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Frontotemporal dementia-associated protein "phosphorylated TDP-43" localizes to atherosclerotic lesions of human carotid and main cerebral arteries2020

    • Author(s)
      Umahara T, Uchihara T, Hirao K, Shimizu S, Hashimoto T, Akimoto J, Kohno M, Hanyu H.
    • Journal Title

      Histol Histopathol

      Volume: 35 Pages: 159-167

    • Related Report
      2019 Research-status Report
    • Peer Reviewed

URL: 

Published: 2018-04-23   Modified: 2023-01-30  

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