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Integrative pathology of Amyloidosis: Exploratory research on the basis of transmission phenomena

Research Project

Project/Area Number 17H04063
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Experimental pathology
Research InstitutionShinshu University

Principal Investigator

Higuchi Keiichi  信州大学, 学術研究院医学系, 教授 (20173156)

Co-Investigator(Kenkyū-buntansha) 森 政之  信州大学, 学術研究院医学系, 准教授 (60273190)
矢崎 正英  信州大学, 学術研究院保健学系, 教授 (70372513)
宮原 大貴  信州大学, 先鋭領域融合研究群バイオメディカル研究所, 助教(特定雇用) (90823287)
澤下 仁子  信州大学, 学術研究院医学系, 助教 (40359732)
亀谷 富由樹  公益財団法人東京都医学総合研究所, 認知症・高次脳機能研究分野, 主席研究員 (70186013)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2019: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2017: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Keywords実験病理学 / アミロイドーシス / 疾患モデル動物 / 老化 / 蛋白質化学 / マウス / 伝播 / リポ蛋白質 / 疾患モデル動 / 蛋白質 / ApoA-II / アミロイド / 病理学
Outline of Final Research Achievements

We investigated "Prion like transmission" and "Age-related disruption of proteostasis" of amyloidosis using mouse AApoAII amyloidosis.
We found fibrillar molecules having amyloidosis inducing activity in white blood cells and serum of amyloid laden mice, and amyloid fibrils made of short ApoA-II without C-terminal in intestine in which the earliest deposition is observed. We believe that more amyloidogenic N-terminal ApoA-II fragments polymerize to amyloid fibri firstl in intestine and blood transports these fibrils to other organs in which fibrils works as templates for full length ApoA-II to make amyloid fibrils.
We used calorie restriction, exercise and treatment with anti-oxidative stress reagents for decelerating aging and revealed that these treatments prevented amyloidosis significantly, We investigated the age-related amyloidosis of C57BL/6 mice that is a standard mouse strain for aging research in various institutes.

Academic Significance and Societal Importance of the Research Achievements

30種類以上報告されているアミロイドーシスには、アミロイド線維がseedとして作用し、自己増殖するという「伝播現象」と、年齢(老化)が最も大きな発症危険因子であるという「共通点」が認められている。本研究では、血球及び血漿中に伝播力を持つ物質が存在すること、腸管で末端が切断されたアミロイド原性が高い前駆タンパク質が最初にアミロイド線維を形成し、その後全身へ伝播することを示したことは、アミロイドーシスに共通した発症抑制方法の開発での意義は大きい。高齢化の進行が進む現状において、老化を遅延させる食事制限、運動、抗酸化剤の投与などが、アミロイドーシスの発症を抑制することを示したことは社会的意義が高い。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (48 results)

All 2019 2018 2017 Other

All Int'l Joint Research (4 results) Journal Article (9 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 8 results,  Open Access: 5 results) Presentation (30 results) (of which Int'l Joint Research: 9 results,  Invited: 12 results) Book (1 results) Remarks (4 results)

  • [Int'l Joint Research] Hebei Medical University,(中国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Baylor College of Medicine(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Children’s Hospital of Hebei Province(中国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] Baylor College of Medicine(米国)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Suppression of mouse AApoAII amyloidosis progression by daily supplementation with oxidative stress inhibitors.2019

    • Author(s)
      Jian Dai , Xin Ding, Hiroki Miyahara, Zhe Xu, Xiaoran Cui, Yuichi Igarashi, Jinko Sawashita, Masayuki Mori, Keiichi Higuchi
    • Journal Title

      Oxid Med Cell Longev

      Volume: 2019 Pages: 1-14

    • DOI

      10.1155/2019/1263274

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The senescence-accelerated mouse as a model for geriatrics and aging biology2019

    • Author(s)
      森 政之、樋口京一
    • Journal Title

      Folia Pharmacologica Japonica

      Volume: 153 Issue: 4 Pages: 179-185

    • DOI

      10.1254/fpj.153.179

    • NAID

      130007630615

    • ISSN
      0015-5691, 1347-8397
    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Suppression of mouse AApoAII amyloidosis progression by daily supplementation with oxidative stress inhibitors.2019

    • Author(s)
      Dai J, Ding X, Miyahara H, Xu Z, Cui X, Igarashi Y, Sawashita J, Mori M, Higuchi K.
    • Journal Title

      Oxidative Medicine and Cellular Longevity

      Volume: 印刷中

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 全身性アミロイドーシスの伝播2019

    • Author(s)
      樋口京一
    • Journal Title

      Dementia Japan

      Volume: 33 Pages: 23-30

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Apolipoprotein A-II induces acute-phase response associated AA amyloidosis in mice through conformational changes of plasma lipoprotein structure.2018

    • Author(s)
      Yang M, Liu Y, Dai J, Li L, Ding X, Xu Z, Mori M, Miyahara H, Sawashita J, Higuchi K.
    • Journal Title

      Sci Rep

      Volume: 8(1) Issue: 1 Pages: 5620-5620

    • DOI

      10.1038/s41598-018-23755-y

    • NAID

      120007113459

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Amyloidosis-inducing activity of blood cells in mouse AApoAII amyloidosis2018

    • Author(s)
      Ding X, Liu Y, Yang M, Li L, Miyahara H, Dai J, Xu Z, Matsumoto K, Mori M, Higuchi K, Sawashita J.
    • Journal Title

      Experimental Animals

      Volume: 67 Issue: 2 Pages: 105-115

    • DOI

      10.1538/expanim.17-0082

    • NAID

      130006733621

    • ISSN
      0007-5124, 1341-1357, 1881-7122
    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Comprehensive proteomic profiles of mouse AApoAII amyloid fibrils provide insights into the involvement of lipoproteins in the pathology of amyloidosis2018

    • Author(s)
      Miyahara H, Sawashita J, Ishikawa E, Yang M, Ding X, Liu Y, Hachiya N, Kametani F, Yazaki M, Mori M, Higuchi K
    • Journal Title

      J Proteomics

      Volume: 172 Pages: 111-121

    • DOI

      10.1016/j.jprot.2017.10.003

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Caloric restriction prevents the progression of murine AApoAII amyloidosis.2017

    • Author(s)
      Sawashita J, Li L, Liu Y, Ding X, Yang M, Xu Z, Higuchi K.
    • Journal Title

      Amyloid

      Volume: 24(sup1) Issue: sup1 Pages: 171-172

    • DOI

      10.1080/13506129.2017.1295948

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Apolipoprotein A-II accelerates reactive AA amyloidosis.2017

    • Author(s)
      Yang M, Liu Y, Li L, Miyahara H, Ding X, Dai J, Sawashita J, Mori M, Higuchi K.
    • Journal Title

      Amyloid

      Volume: 24(sup1) Issue: sup1 Pages: 147-148

    • DOI

      10.1080/13506129.2017.1295949

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Presentation] 培養細胞系におけるAApoAIIアミロイド沈着モデルの確立2019

    • Author(s)
      宮原 大貴, 代 健, 崔 小冉, 五十嵐 佑一、劉 暢, 、森 政之、樋口京一
    • Organizer
      第7回日本アミロイドーシス学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] クルクミン摂取はAApoAIIアミロイドーシスの発症を促進する? 肝臓機能への影響と促進メカニズムの検討2019

    • Author(s)
      代 健、崔 小冉、五十嵐 佑一、宮原 大貴、森 政之、樋口 京一
    • Organizer
      第7回日本アミロイドーシス学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 運動によるAApoAIIアミロイドーシス抑制効果の解析2019

    • Author(s)
      崔 小冉、澤下 仁子、代 健、宮原 大貴、五十嵐 佑一、霍 佳、丁 欣、森 政之、樋口 京一
    • Organizer
      第7回日本アミロイドーシス学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] C57BL/6JマウスにおけるAApoAIIアミロイドーシスの特徴及び伝播との関係の検討2019

    • Author(s)
      李 瑩、代 健、 崔 小冉、 五十嵐 佑一、 宮原 大貴、 森 政之、 樋口 京一
    • Organizer
      第7回日本アミロイドーシス学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] クルクミン摂取はAApoAIIアミロイドーシスの発症を促進する:促進メカニズムの検討2019

    • Author(s)
      代 健、崔 小冉、五十嵐 佑一、李 瑩、宮原 大貴、森 政之、樋口 京一
    • Organizer
      第14回日本臨床ストレス応答学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Mouse systemic amyloidosis ; pathogenesis and prevention.2019

    • Author(s)
      Keiichi Higuchi
    • Organizer
      Towards a cure for amyloid diseases. A successful example of precision and translational medicine.
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Suppressing the progression of mouse AApoAII amyloidosis by daily supplementation with oxidative stress inhibitors.2019

    • Author(s)
      Jian Dai, Xiaoran Cui, Yuichi Igarashi, Ying Li, Hiroki Miyahara, Masayuki Mori, Keiichi Higuchi
    • Organizer
      Towards a cure for amyloid diseases: a successful example of precision and translational medicine.
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A cell culture system of mouse AApoAII amyloid deposition.2019

    • Author(s)
      Hiroki Miyahara, Xiaoran Cui, Yuichi Igarashi, Ying Li, Jian Dai, Masayuki Mori, Keiichi Higuchi.
    • Organizer
      Towards a cure for amyloid diseases: a successful example of precision and translational medicine.
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Seeding and transmission phenomena in systemic amyloidosis.2019

    • Author(s)
      Keiichi Higuchi
    • Organizer
      Ulm Meeting-Biophysics of Amyloid Formation. Ulm University,
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Prion-like transmission of mouse systemic AApoAII and AA Amyloidoses.2018

    • Author(s)
      Keiichi Higuchi, Hiroki Miyahara
    • Organizer
      Asian Pacific Prion Symposium 2018 (APPS2018),
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 老化研究のためのモデルマウス-老化促進モデルマウスを軸にして-2018

    • Author(s)
      樋口 京一
    • Organizer
      第65回日本実験動物学会総会(大会)
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 伝播現象の把握からアミロイドーシスでの新たな治療法を探る2018

    • Author(s)
      樋口 京一
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] マウス AApoAII アミロイド線維の包括的なプロテオーム分析結果はアミロイドーシスの病理におけるリポタンパク質の関与を示唆する2018

    • Author(s)
      宮原 大貴、森 政之、樋口 京一
    • Organizer
      第18回日本蛋白質科学会年会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Comprehensive proteomic analysis of mouse AApoAII amyloidosis.2018

    • Author(s)
      Hiroki Miyahara , Masayuki Mori, Keiichi Higuchi
    • Organizer
      Asian Pacific Prion Symposium 2018 (APPS2018),
    • Related Report
      2018 Annual Research Report
  • [Presentation] 酸化ストレス抑制剤の継続摂取によるマウスAApoAIIアミロイドーシスの進行抑制効果(2)2018

    • Author(s)
      代 健, 丁 欣, 宮原大貴, 徐 哲, 崔 小冉, 五十嵐 祐一, 澤下 仁子, 森 政之, 樋口 京一
    • Organizer
      第6回日本アミロイドーシス研究会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 運動によるAApoAIIアミロイドーシス抑制効果とメカニズムの解析2018

    • Author(s)
      崔 小冉, 澤下仁子、 代 健, 霍 佳, 五十嵐祐一, 丁 欣, 宮原大貴, 森 政之, 樋口 京一
    • Organizer
      第6回日本アミロイドーシス研究会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Comprehensive proteomic profiles of mouse AApoAII amyloid fibrils provide insights into the involvement of lipoproteins in the pathology of amyloidosis.2018

    • Author(s)
      Hiroki Miyahara, Xin Ding, Jinko Sawashita, Masayuki Mori, Keiichi Higuchi
    • Organizer
      The XVIth International Symposium on Amyloidosis
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Amyloidosis-inducing activity of blood components in mouse AApoAII amyloidosis.2018

    • Author(s)
      Xin Ding, Yingye Liu, Mu Yang, Lin Li, Hiroki Miyahara, Jian Dai, Zhe Xu, Kiyoshi Matsumoto, Masayuki Mori, Jinko Sawashita, Keiichi Higuchi
    • Organizer
      The XVIth International Symposium on Amyloidosis
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Suppressing the progression of mouse AApoAII amyloidosis by daily supplementation with oxidative stress inhibitors.2018

    • Author(s)
      Jian Dai, Xin Ding, Hiroki Miyahara, Zhe Xu, Xiaoran Cui, Yuichi Igarashi, Jinko Sawashita, Keiichi Higuchi
    • Organizer
      The XVIth International Symposium on Amyloidosis
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 老化研究のためのモデルマウスー老化促進モデルマウスを軸にしてー2018

    • Author(s)
      樋口京一
    • Organizer
      第65回日本実験動物学会総会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 伝播現象の把握からアミロイドーシスの新たな治療法を探る2018

    • Author(s)
      樋口京一
    • Organizer
      第91回日本生化学大会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Coenzyme Q10 could improve healthy aging. New findings obtained in mouse models and in vitro studies.2018

    • Author(s)
      Keiichi Higuchi, Zhe Xu, Jia Huo, Kazunori Hosoe, Hiroshi Kubo, Hiroki Miyahara, Jian Dai, Masayuki Mori, Jinko Sawashita
    • Organizer
      The 9th Conference of the International Coenzyme Q10 Association.
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] モデル動物を用いた抗老化サプリメントの検討:コエンザイムQ10の作用メカニズム。2017

    • Author(s)
      樋口京一、徐 哲、霍 佳、田 耕、澤下仁子
    • Organizer
      第71回日本栄養・食糧学会大会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 摂餌制限はマウスAApoAIIアミロイドーシスの全身での進行を軽減する。2017

    • Author(s)
      澤下仁子、李 琳、丁 欣、徐 哲、宮原大貴、樋口京一
    • Organizer
      老化促進モデルマウス(SAM)学会第32回学術大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 酸化ストレス抑制剤の継続摂取によるマウスAApoAIIアミロイドーシスの進行抑制効果。2017

    • Author(s)
      代 健、丁 欣、宮原大貴、徐 哲、崔 小冉、五十嵐佑一、澤下仁子、樋口京一
    • Organizer
      老化促進モデルマウス(SAM)学会第32回学術大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Apolipoprotein A-IIが反応性(AA)アミロイドーシスの病態に及ぼす効果。2017

    • Author(s)
      楊 沐、劉 穎業、李 琳、宮原大貴、丁 欣、代 健、森 政之、澤下仁子、樋口京一
    • Organizer
      老化促進モデルマウス(SAM)学会第32回学術大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] アミロイドーシス研究のための動物モデル。2017

    • Author(s)
      樋口京一
    • Organizer
      第5回日本アミロイドーシス研究会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 酸化ストレス抑制剤の継続摂取によるマウスAApoAIIアミロイドーシスの進行抑制効果。2017

    • Author(s)
      代 健、丁 欣、宮原大貴、徐 哲、崔 小冉、五十嵐佑一、澤下仁子、樋口京一
    • Organizer
      第5回日本アミロイドーシス研究会学術大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 酸化ストレス抑制剤の継続摂取によるマウスAApoAIIアミロイドーシスの進行抑制。2017

    • Author(s)
      代 健、丁 欣、宮原大貴、徐 哲、崔 小冉、五十嵐佑一、樋口京一, 澤下仁子
    • Organizer
      第12回臨床ストレス応答学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 全身性アミロイドーシスの伝播:異常構造アミロイドタンパク質はプリオンのように自己増殖するか?2017

    • Author(s)
      樋口京一
    • Organizer
      第36回日本認知症学会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Book] アミロイドーシスの最新情報 (全身性アミロイドーシスの疾患感受性と個体間伝播 )2017

    • Author(s)
      樋口京一、澤下仁子。全身性アミロイドーシスの疾患感受性と個体間伝播。
    • Total Pages
      250
    • Publisher
      医歯薬出版
    • Related Report
      2017 Annual Research Report
  • [Remarks] 信州大学医学部加齢生物学教室ホームページ

    • URL

      http://www.shinshu-u.ac.jp/faculty/medicine/department/doctor/grdkarei/i-byotai/

    • Related Report
      2019 Annual Research Report
  • [Remarks] 信州大学医学部加齢生物学教室ホームページ

    • URL

      http://www.shinshu-u.ac.jp/faculty/medicine/department/doctor/grdkarei/i-byotai/paper2015.htm

    • Related Report
      2018 Annual Research Report
  • [Remarks] 信州大学情報オンラインシステムSOAR

    • URL

      http://soar-rd.shinshu-u.ac.jp/profile/ja.gCfUPmAh.html

    • Related Report
      2018 Annual Research Report
  • [Remarks] 信州大学医学系研究科疾患予防医科学系専攻加齢生物学教室ホームページ

    • URL

      http://www.shinshu-u.ac.jp/faculty/medicine/department/doctor/grdkarei/i-byotai/

    • Related Report
      2017 Annual Research Report

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Published: 2017-04-28   Modified: 2022-05-23  

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