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High dimensional analysis of neurovasculature to reveal molecular mechanism of aged or neurodegenerative brain

Research Project

Project/Area Number 19K07831
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 51030:Pathophysiologic neuroscience-related
Research InstitutionInstitute of Physical and Chemical Research (2021-2022)
Juntendo University (2019-2020)

Principal Investigator

Fukuhara Takeshi  国立研究開発法人理化学研究所, 脳神経科学研究センター, 研究員 (20359673)

Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsパーキンソン病 / 炎症 / 免疫 / アストロサイト / 老化 / 血管 / イムノトキシン / イムノリポソーム / 機能性抗体 / 炎症血管 / モノクローナル抗体 / PARK2 / Parkin / Rotenone / 抗体
Outline of Research at the Start

本研究は、脳血管を包括的かつ構成的に理解する目的で、1細胞レベルかつプロテオミックレベルでのサブセット規定を基盤に、トランスクリプトーム解析データと細胞アトラスとの照合・統合により老化・病態脳血管の深い洞察と分子メカニズムを得ようとする。同様の研究は国内外で開始されていない。特に老化・PD病態における脳血管サブセットの変質を、血中因子の脳血管への作用から明らかにする目的で、独自のPD患者炎症バイオマーカーの知見と融合して課題解決を目指す。

Outline of Final Research Achievements

This study aimed to unravel the underlying mechanism of Parkinson’s disease, especially at the viewpoint from neurovascular-immune interaction. To do this, various inflammatory markers of vasculature or myeloid cells were tested in aged mice cohort as well as PARK2-deficient cohort. Due to the progressive phenotype of PARK2 mutation in patient, the responsible mice mutant was employed in this study for further analysis. Besides immunohistochemical analysis, RNA-seq analysis of brain was performed against 16 or 28 months old cohort. Although there are no prominent genes expressed between wildtype or PARK2 mutant, aging itself forced to increase a few marker including C4b that are one of complement factors. In PARK2 mutant background, we observed age from 16 to 28 monts with increased expression of GFAP (astrocyte marker) and Lyz2 (myeloid marker). These dataset suggest that a subtle change in glia promoted age-related chronic inflammation.

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病は根治療法のない神経変性疾患であり、家族性および孤発性のいずれにおいても対処療法しか治療法がない。このため、疾患修飾療法としての先制医療が期待されている。近年では脳内炎症に限らず、腸管をはじめとした末梢臓器の炎症がパーキンソン病の進行に寄与していると考えられる報告があり、注目を集めている。本研究は、脳と末梢臓器をつなぐ脳血管に着目し、炎症血管マーカーなどを検索した。老化に対する治療法やパーキンソン病の治療作用点として妥当性の検証が必要となるが、老化に連動して発現上昇するC4bやLyz2を分子標的とした創薬探索が今後期待される。

Report

(4 results)
  • 2022 Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (19 results)

All 2021 2020 2019

All Journal Article (8 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 7 results,  Open Access: 5 results) Presentation (9 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Book (2 results)

  • [Journal Article] α-Synuclein Seeding Assay Using RT-QuIC.2021

    • Author(s)
      Okuzumi Ayami、Hatano Taku、Fukuhara Takeshi、Ueno Shinichi、Nukina Nobuyuki、Imai Yuzuru、Hattori Nobutaka
    • Journal Title

      Methods Mol Biol.

      Volume: 2322 Pages: 3-16

    • DOI

      10.1007/978-1-0716-1495-2_1

    • ISBN
      9781071614945, 9781071614952
    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Anti-CD321 antibody immunotherapy protects liver against ischemia and reperfusion-induced injury.2021

    • Author(s)
      Enzhi Yin, Takeshi Fukuhara, Kazuyoshi Takeda, Yuko Kojima, Kyoko Fukuhara, Kenichi Ikejima, Hisashi Bashuda, Jiro Kitaura, Hideo Yagita, Ko Okumura, Koichiro Uchida
    • Journal Title

      Scientific Reports

      Volume: 6322 Issue: 1 Pages: 1-10

    • DOI

      10.1038/s41598-021-85001-2

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Novel method for screening functional antibody with comprehensive analysis of its immunoliposome2021

    • Author(s)
      Hamamichi Shusei、Fukuhara Takeshi、Umeda Izumi O.、Fujii Hirofumi、Hattori Nobutaka
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 1-13

    • DOI

      10.1038/s41598-021-84043-w

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Immunotoxin screening system: A rapid and direct approach to obtain functional antibodies with internalization capacities2020

    • Author(s)
      Shusei Hamamichi, Takeshi Fukuhara, Nobutaka Hattori
    • Journal Title

      Toxins

      Volume: 12 Issue: 10 Pages: 1-15

    • DOI

      10.3390/toxins12100658

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Demon slayer? Targeting myeloid cells for modulating neuroinflammation2020

    • Author(s)
      Takeshi Fukuhara, Taku Hatano, Nobutaka Hattori
    • Journal Title

      Bio clinica

      Volume: 9 Pages: 153-155

    • Related Report
      2020 Research-status Report
  • [Journal Article] Prenatal exposure to valproic acid is associated with altered neurocognitive function and neurogenesis in the dentate gyrus of male offspring rats.2019

    • Author(s)
      Tomoya Kinjo, Masanobu Ito, Tatsunori Seki, Takeshi Fukuhara, Kuerban Bolati, Heii Arai, Toshihito Suzuki
    • Journal Title

      Brain Research

      Volume: 1723 Pages: 146403-146403

    • DOI

      10.1016/j.brainres.2019.146403

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Multi-year whole-blood transcriptome data for the study of onset and progression of Parkinson's Disease.2019

    • Author(s)
      Valentine MNZ, Hashimoto K, Fukuhara T, Saiki S, Ishikawa KI, Hattori N, Carninci P.
    • Journal Title

      Sci Data

      Volume: 6 Issue: 1 Pages: 1-7

    • DOI

      10.1038/s41597-019-0022-9

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Interleukin-13 receptor α2 is a novel marker and potential therapeutic target for human melanoma.2019

    • Author(s)
      Okamoto H*, Yoshimatsu Y*, Tomizawa T*, Kunita A*, Takayama R*, Morikawa T, Komura D, Takahashi K, Oshima T, Sato M, Komai M, Podyma-Inoue KA, Uchida H, Hamada H, Fujiu K, Ishikawa S, Fukayama M, Fukuhara T, Watabe T. (* equal contributor)
    • Journal Title

      Sci Rep.

      Volume: 9 Issue: 1 Pages: 1281-1281

    • DOI

      10.1038/s41598-019-39018-3

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Novel method for screening functional antibody and its application toward generating drug delivery modality.2020

    • Author(s)
      Takeshi Fukuhara
    • Organizer
      第93回日本生化学会
    • Related Report
      2020 Research-status Report
  • [Presentation] 薬物送達能を示す機能性抗体の探索技術とイムノリポソーム開発による機能解析2019

    • Author(s)
      福原武志、濱道修生、服部信孝
    • Organizer
      第35回日本DDS学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 脳血管内皮細胞の多次元解析による老化に特徴的な亜集団の同定2019

    • Author(s)
      福原武志、濱道修生、服部信孝
    • Organizer
      Neuro2019, 第42回日本神経科学会
    • Related Report
      2019 Research-status Report
  • [Presentation] alpha-synucleinの伝播抑制因子の探索と複合療法を開発2019

    • Author(s)
      奥住文美、波田野琢、福原武志、常見泰司、貫名信行、服部信孝
    • Organizer
      MSDJ2019, パーキンソン病運動障害疾患コングレス
    • Related Report
      2019 Research-status Report
  • [Presentation] Effects of foreign element contents on functional a-C:H film structure for biomedical applications2019

    • Author(s)
      Y. Ohgoe, T. Fukuhara, N. Miyata, T. Yaguchi, A. Homma, and K. Hirakuri
    • Organizer
      7th International Symposium on Surfaces and Interfaces for Biomaterials
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Screening technology and application of functional antibody for brain diseases2019

    • Author(s)
      Takeshi Fukuhara
    • Organizer
      13th International Symposium on Nanomedicine, ISNM2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] CD321 mAb (90G4) protects liver via inhibiting neutrophil infiltration in murine hepatic ischemia reperfusion model2019

    • Author(s)
      Enzhi Yin, Takeshi Fukuhara, Kazuyoshi Takeda, Hisashi Bashuda, Koichiro Uchida
    • Organizer
      第48回日本免疫学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 血管新生阻害剤に対する薬剤耐性を回避する新たな腫瘍兵糧攻め療法の開発2019

    • Author(s)
      加藤智尋、北村成史、徳永正之、濱田庸、鳩山恵一朗、高野真由美、福原武志、今井陽介、権田幸祐
    • Organizer
      第27回日本血管生物医学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 悪性黒色腫の血管新生及び腫瘍形成能におけるIL13Rα2の役割2019

    • Author(s)
      高山莉那、岡本勇人、吉松康裕、富澤泰志、国田朱子、高橋和樹、井上 カタジナアンナ、深山正久、福原武志、渡部徹郎
    • Organizer
      第27回日本血管生物医学会学術集会
    • Related Report
      2019 Research-status Report
  • [Book] 機能性抗体の探索から新しい治療モダリティの創薬へ ー神経変性疾患載せらのスティクス開発に有望なエピトープを探して2019

    • Author(s)
      福原武志
    • Publisher
      北隆館 Precision Medicine
    • Related Report
      2019 Research-status Report
  • [Book] 機能性抗体の探索とイムノリポソーム開発による神経変性疾患の創薬創発へ2019

    • Author(s)
      福原武志、服部信孝
    • Publisher
      北隆館 Precision Medicine
    • Related Report
      2019 Research-status Report

URL: 

Published: 2019-04-18   Modified: 2024-01-30  

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