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Establishment of neurodegeneration-expansion by death cell-live cell signal transduction and development of new therapeutics targeting on the signal

Research Project

Project/Area Number 19H01042
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 52:General internal medicine and related fields
Research InstitutionTokyo Medical and Dental University

Principal Investigator

Okazawa Hitoshi  東京医科歯科大学, 難治疾患研究所, 教授 (50261996)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥45,630,000 (Direct Cost: ¥35,100,000、Indirect Cost: ¥10,530,000)
Fiscal Year 2021: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
Fiscal Year 2020: ¥14,950,000 (Direct Cost: ¥11,500,000、Indirect Cost: ¥3,450,000)
Fiscal Year 2019: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Keywords神経変性疾患 / アルツハイマー病 / 前頭側頭葉変性症 / ネクローシス / 変性拡散 / 神経変性 / 変性拡散仮説 / 死細胞・生細胞間シグナル伝達 / 認知症 / YAP / HMGB1 / TRIAD
Outline of Research at the Start

本研究の目的は以下の3点である。1)神経変性疾患における新規ネクローシスの時間軸上の定義を行う。2)新規ネクローシスに至る上流の病態機序を解明する。3)ネクローシス細胞が引き起こす下流シグナル『変性拡散』の概念確立を目指す。本研究によって、細胞死が単に複数病態が最終的に帰結する終末段階であるという、受動的な『終末期細胞死仮説』から、早期に細胞死が起きて周辺神経細胞の病態カスケード(機能障害経路など)を刺激して変性を拡散・加速するという、能動的な『早期細胞死依存的な変性拡散仮説』にパラダイムシフトすることが出来る。すなわち、神経変性疾患の細胞死についての基本的コンセプトが修正される。

Outline of Final Research Achievements

In this project, we revealed the time point when the new type of necrosis named TRIAD initiates during the course of neurodegenerative diseases such as Alzheimer’s disease and frontotemporal lobar degeneration. Next, we revealed the upstream pathway of TRIAD by using biochemical, genetic and cell biological experiments. Furthermore, we revealed how the factors released from TRIAD or the membrane molecules of TRIAD neurons induced secondary necrosis in the downstream.

Academic Significance and Societal Importance of the Research Achievements

上記の解析を疾患横断的に実施・比較することで、得られた結果に基づいて、神経変性疾患における新規ネクローシスの時間軸上の位置付けを定義すると同時に、死細胞・生細胞間シグナル伝達の観点から『変性』の新たな概念を樹立することができた。また、最終的に、シグナル経路遮断を行い、細胞レベル、個体レベル(病理および認知機能等の行動解析)で回復が見られるかを検討したところ、候補となるシグナル経路の病的意義を実証することができた。これにより、従来の戦略とは異なる治療法の開発が可能となった。

Report

(4 results)
  • 2021 Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Comments on the Screening Results   Annual Research Report
  • Research Products

    (58 results)

All 2021 2020 2019 Other

All Int'l Joint Research (6 results) Journal Article (11 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 5 results,  Open Access: 4 results) Presentation (32 results) (of which Int'l Joint Research: 9 results,  Invited: 23 results) Remarks (1 results) Patent(Industrial Property Rights) (8 results) (of which Overseas: 4 results)

  • [Int'l Joint Research] Icahn School of Medicine at Mount Sinai(米国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] Barrow Neurological Institute(米国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] King's College London(英国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] National University of Singapore(シンガポール)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Barrow Neurological Institute(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] King's College London(英国)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)12021

    • Author(s)
      Daniel J Klionsky、Shu Aizawa、Amal Kamal Abdel-Aziz、Sara Abdelfatah、Mahmoud Abdellatif、Asghar Abdoli、Steffen Abel、Hagai Abeliovich、Marie H Abildgaard、Yakubu Princely Abudu、Abraham Acevedo-Arozena、Iannis E Adamopoulos、Khosrow Adeli、Timon E Adolph、Annagrazia Adornetto、Elma Aflaki、Galila Agam et al.
    • Journal Title

      Autophagy

      Volume: 17 Issue: 1 Pages: 1-382

    • DOI

      10.1080/15548627.2020.1797280

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Role of the <i>Drosophila</i> YATA protein in the proper subcellular localization of COPI revealed by <i>in vivo</i> analysis2020

    • Author(s)
      Saito Maiko、Nakayama Minoru、Fujita Kyota、Uchida Atsuko、Yano Hiroyuki、Goto Satoshi、Okazawa Hitoshi、Sone Masaki
    • Journal Title

      Genes & Genetic Systems

      Volume: 95 Issue: 6 Pages: 303-314

    • DOI

      10.1266/ggs.20-00027

    • NAID

      130008002033

    • ISSN
      1341-7568, 1880-5779
    • Year and Date
      2020-12-01
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ダウンストリームを治療する2020

    • Author(s)
      田中 ひかり、岡澤 均
    • Journal Title

      医学のあゆみ

      Volume: 273 Pages: 93-97

    • Related Report
      2020 Annual Research Report
  • [Journal Article] アルツハイマー病態に於ける細胞内アミロイド、細胞死、細胞外アミロイド凝縮の時間的関係2020

    • Author(s)
      岡澤 均
    • Journal Title

      神経治療学

      Volume: 37

    • NAID

      130007922492

    • Related Report
      2020 Annual Research Report
  • [Journal Article] ポストコロナ社会における脳神経疾患の診療と研究2020

    • Author(s)
      岡澤 均
    • Journal Title

      脳神経疾患克服に向けた研究推進の提言2020

      Volume: - Pages: 17-17

    • Related Report
      2020 Annual Research Report
  • [Journal Article] 脊髄小脳失調症2020

    • Author(s)
      田中 ひかり、岡澤 均
    • Journal Title

      Clinical Neuroscience

      Volume: 38 Pages: 365-368

    • Related Report
      2019 Annual Research Report
  • [Journal Article] YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology2020

    • Author(s)
      Tanaka Hikari, Tagawa Kazuhiko, Okazawa Hitoshi et al.
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 507-507

    • DOI

      10.1038/s41467-020-14353-6

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] PQBP1, an intellectual disability causative gene, affects bone development and growth2020

    • Author(s)
      Yang Shin-Sheng、Ishida Takayoshi、Fujita Kyota、Nakai Yuta、Ono Takashi、Okazawa Hitoshi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 523 Issue: 4 Pages: 894-899

    • DOI

      10.1016/j.bbrc.2019.12.097

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 脊髄小脳失調症とYAPdeltaC2019

    • Author(s)
      近藤 和, 藤田 慶大, 岡澤 均
    • Journal Title

      Clinical Neuroscience

      Volume: 37 Pages: 1007-1010

    • Related Report
      2019 Annual Research Report
  • [Journal Article] 発達障害原因遺伝子PQBP1はアルツハイマー病態を制御する2019

    • Author(s)
      田中 ひかり、岡澤 均
    • Journal Title

      ケミカルバイオロジー

      Volume: 12 Pages: 12-12

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Frameshift PQBP-1 mutants K192Sfs*7 and R153Sfs*41 implicated in X-linked intellectual disability form stable dimers2019

    • Author(s)
      Rahman Shah Kamranur、Okazawa Hitoshi、Chen Yu Wai
    • Journal Title

      Journal of Structural Biology

      Volume: 206 Issue: 3 Pages: 305-313

    • DOI

      10.1016/j.jsb.2019.04.003

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Deciphering and tacking the ultra-early phase pathology of Alzheimer’s disease2021

    • Author(s)
      Hitoshi Okazawa
    • Organizer
      The 15th International Conference on Alzheimer’s and Parkinson’s Diseases
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 動的分子ネットワーク解析を用いたFTLD-AD間における共通コア病態の予測2021

    • Author(s)
      本間 秀典、藤田 慶大、田川 一彦、岡澤 均
    • Organizer
      第13回 CBIR/ONSA/大学院セミナー共催若手インスパイアシンポジウム
    • Related Report
      2020 Annual Research Report
  • [Presentation] 発達障害原因遺伝子PQBP1はアルツハイマー病態を制御する2020

    • Author(s)
      田中 ひかり、近藤 和、陳 西貴、本間 秀典、藤田 慶大、田川 一彦、岡澤 均
    • Organizer
      第39回日本認知症学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] YAP依存的ネクローシスは超早期アルツハイマー病態を制御する2020

    • Author(s)
      田中 ひかり、本間 秀典、藤田 慶大、近藤 和、金 暁岑、田川 一彦、岡澤 均
    • Organizer
      第39回日本認知症学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] アルツハイマー病の細胞死は、いつ起きるのか?2020

    • Author(s)
      岡澤 均
    • Organizer
      第42回神経組織培養研究会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] アルツハイマー病態に於ける細胞内アミロイド、細胞死、細胞外アミロイド凝縮の時間的関係2020

    • Author(s)
      岡澤 均
    • Organizer
      第38回日本神経治療学会学術集会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Phosphorylation of SRRM2 leads to synaptic pathology at ultra-early phase of Alzheimer's disease2020

    • Author(s)
      Hikari Tanaka, Kanoh Kondo, Xigui Chen, Hidenori Homma, Kazuhiko Tagawa, Takaomi Saido, Shin-ichi Muramatsu, Kyota Fujita, Hitoshi Okazawa
    • Organizer
      61st Annual Meeting of the Japanese Society of Neurology
    • Related Report
      2020 Annual Research Report
  • [Presentation] ハンチントン病の治療開発の動向2020

    • Author(s)
      岡澤 均
    • Organizer
      第61回日本神経学会学術大会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] YAP-dependent necrosis regulates early stages of Alzheimer’s disease pathology2020

    • Author(s)
      Hikari Tanaka, Hidenori Homma, Kyota Fujita, Kanoh Kondo, Jin Xiaocen, Kazuhiko Tagawa, Hitoshi Okazawa
    • Organizer
      The 43rd Annual Meeting of the Japan Neuroscience Society
    • Related Report
      2020 Annual Research Report
  • [Presentation] Discovery of new pathologies and development of new therapeutics based on molecular network analysis against Alzheimer's disease2020

    • Author(s)
      Hitoshi Okazawa
    • Organizer
      The 43rd Annual Meeting of the Japan Neuroscience Society
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 遺伝子治療によるアルツハイマー治療の可能性2020

    • Author(s)
      岡澤 均
    • Organizer
      第一期バイオインベストメントギルド第9回セミナー
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 神経変性疾患の分子病態2020

    • Author(s)
      岡澤 均
    • Organizer
      横浜市立大学医学部医学科特別講義
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Development of gene therapies of neurodegenerative diseases targeting new pathological mechanisms2020

    • Author(s)
      岡澤 均
    • Organizer
      AMED -Gene & Cell Therapy Symposium-遺伝子・細胞治療シンポジウム-
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 神経変性疾患の病態に基づく遺伝子治療2020

    • Author(s)
      岡澤 均
    • Organizer
      第2回自治医科大学遺伝子治療研究センター(JMU-CGTR)シンポジウム2020
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 網羅的解析が示唆する変性疾患の超早期病態2020

    • Author(s)
      岡澤 均
    • Organizer
      第23回東京 脳・神経セミナー
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology2020

    • Author(s)
      田中 ひかり、本間 秀典、藤田 慶大、近藤 和、Xiaocen Jin、田川 一彦、岡澤 均
    • Organizer
      第12回 CBIR/ONSA/大学院セミナー共催若手インスパイアシンポジウム
    • Related Report
      2019 Annual Research Report
  • [Presentation] Ultra-early phase pathology of neurodegeneration2019

    • Author(s)
      Hitoshi Okazawa
    • Organizer
      China-Japan High-end Forum on Medical and Health Cooperation
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Alzheimer’s disease and Autophagy2019

    • Author(s)
      Hitoshi Okazawa
    • Organizer
      第38回日本認知症学会学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] New therapeutics development against ultra-early phase AD pathology2019

    • Author(s)
      Hitoshi Okazawa
    • Organizer
      第38回日本認知症学会学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] HMGB1 and Neurodegeneration2019

    • Author(s)
      Hitoshi Okazawa
    • Organizer
      9th International DAMPs and Alarmins Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Targeting HMGB1-mediated expansion of neurodegeneration at the ultra-early phase pathology of Alzheimer’s disease2019

    • Author(s)
      Hitoshi Okazawa
    • Organizer
      AsCNP2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] アルツハイマー病の新規病態と遺伝子治療法の発見2019

    • Author(s)
      岡澤 均
    • Organizer
      創薬薬理フォーラム第27回シンポジウム
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Ser46-phosphorylated MARCKS is a common mechanism of pre-aggregation neurite degeneration in across multiple dementia2019

    • Author(s)
      Kyota Fujita, Hidenori Homma, Kanoh Kondo, Kazuhiko Tagawa, Hitoshi Okazawa
    • Organizer
      NEURO2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The intellectual disability gene PQBP1 rescues Alzheimer's disease pathology2019

    • Author(s)
      Hikari Tanaka, Kanoh Kondo, Xigui Chen, Hidenori Homma, Kazuhiko Tagawa, Aurelian Kerever, Shigeki Aoki, Takashi Saito, Takaomi Saido, Shin-ichi Muramatsu, Kyota Fujita, Hitoshi Okazawa
    • Organizer
      NEURO2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Research and development of neurodegenerative diseases based on the all Japan Brain Bank Network2019

    • Author(s)
      Hitoshi Okazawa
    • Organizer
      NEURO2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Gene therapy for spinocerebellar ataxia2019

    • Author(s)
      Hitoshi Okazawa
    • Organizer
      The 25th Annual Meeting of Japan Society of Gene and Cell Therapy
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] アルツハイマー病の遺伝子治療の可能性2019

    • Author(s)
      岡澤 均
    • Organizer
      第24回認知神経科学会学術集会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 発達障害原因遺伝子PQBP1はアルツハイマー病態を制御する2019

    • Author(s)
      田中 ひかり、近藤 和、陳 西貴 、本間 秀典、田川 一彦、Aurelian Kerever、青木 茂樹、斉藤 貴志、西道 隆臣、村松 慎一、藤田 慶大、岡澤 均
    • Organizer
      第60回日本神経学会学術大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Gene therapy against SCA1 based on the molecular pathomechanism2019

    • Author(s)
      Hitoshi Okazawa
    • Organizer
      60th Annual Meeting Of The Japanese Society of Neurology
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 認知症の新たな治療戦略と遺伝子治療の可能性2019

    • Author(s)
      岡澤 均
    • Organizer
      第60回日本神経学会学術大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Targeting Tyro3 ameliorates a model of PGRN-mutant FTLD-TDP via tau-mediated synaptic pathology2019

    • Author(s)
      Kyota Fujita, Xigui Chen, Hidenori Homma, Kazuhiko Tagawa, Hitoshi Okazawa
    • Organizer
      第60回日本神経学会学術大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] New Treatment Strategies in Huntington’s Disease and Other Chorea2019

    • Author(s)
      Hitoshi Okazawa
    • Organizer
      The 6th Asian and Oceanian Parkinson’s Disease and Movement Disorders Congress 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Remarks] 「アルツハイマー病の超早期細胞死の解明と新たな治療標的を発見」

    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] 前頭側頭葉変性症の予防又は治療剤2020

    • Inventor(s)
      岡澤 均
    • Industrial Property Rights Holder
      岡澤 均
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-204343
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report
  • [Patent(Industrial Property Rights)] 軽度認知障害の予防又は治療剤2020

    • Inventor(s)
      岡澤 均
    • Industrial Property Rights Holder
      岡澤 均
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] 軽度認知障害の診断マーカー2020

    • Inventor(s)
      岡澤 均
    • Industrial Property Rights Holder
      岡澤 均
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] pSer46-MARCKSを認識するモノクローナル抗体の配列2019

    • Inventor(s)
      岡澤 均
    • Industrial Property Rights Holder
      岡澤 均
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] ヒトHMGB1に特異的に結合するヒトモノクローナル抗体、及びそれを含有するアルツハイマー病を治療又は予防するための医薬組成物2019

    • Inventor(s)
      岡澤 均
    • Industrial Property Rights Holder
      岡澤 均
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] アルツハイマー病及び前頭側頭葉変性症の診断方法、診断薬、治療薬、及びこれら薬剤のスクリーニング方法2019

    • Inventor(s)
      岡澤 均
    • Industrial Property Rights Holder
      岡澤 均
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-160228
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] 軽度認知障害の予防又は治療剤2019

    • Inventor(s)
      岡澤 均
    • Industrial Property Rights Holder
      岡澤 均
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-145259
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] 軽度認知障害の診断マーカー2019

    • Inventor(s)
      岡澤 均
    • Industrial Property Rights Holder
      岡澤 均
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-112658
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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