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Search for neuronal cell death-inhibiting drugs for Alzheimer's disease-relevant signal transduction

Research Project

Project/Area Number 22590247
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionTokyo Medical University

Principal Investigator

HASHIMOTO Yuuichi  東京医科大学, 医学部, 講師 (00317330)

Co-Investigator(Renkei-kenkyūsha) MATSUOKA Masaaki  東京医科大学, 医学部, 教授 (70222297)
Project Period (FY) 2010 – 2012
Project Status Completed (Fiscal Year 2012)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsアルツハイマー病 / 神経細胞死 / アミロイド前駆体蛋白質 / プレセニリン / ヒューマニン / アミロイド前駆体タンパク質 / 神経変性疾患 / サイトカイン / 細胞内シグナル伝達 / 受容体 / 治療薬 / 細胞内シグナル伝
Research Abstract

In this research program, we have examined the neuronal cell death mechanism underlysing Alzhemer’s disease (AD), and identified an antagonist of Humanin (HN) which inhibited AD-relevant neuronal cell death and an endogenous agonist of HN receoptor complex composed of WSX-1, ciliary neurotrophic factor receptor/gp130. The results were: (1) MOCA is the key molecule that unifies APP-mediated death signal to PS-mediated death signal, (2) V-set transmembrane domain containing 2 like inhibited HN’s activity via direct binding, and (3) A series of experiments also showed that calmodulin-like skin protein (CLSP), highly expressed in skin tissues, is transported across blood-brain barrier to the central nervous system. CLSP inhibited familial AD-linked V642I-APP-induced neuronal cell death via its binding to HN receptor following activation of JAK2/STAT3 axisThese results suggest that CLSP play a main role in inhibiting AD-related neuronal death and dysfunction in vivo as a physiological defense factor.

Report

(4 results)
  • 2012 Annual Research Report   Final Research Report ( PDF )
  • 2011 Annual Research Report
  • 2010 Annual Research Report
  • Research Products

    (14 results)

All 2013 2012 2011 2010 Other

All Journal Article (6 results) (of which Peer Reviewed: 6 results) Presentation (6 results) Remarks (2 results)

  • [Journal Article] Secreted calmodulin-like skin protein inhibits neuronal death in cell-based Alzheimer's disease models via the heterotrimeric Humanin receptor2013

    • Author(s)
      Hashimoto Y, Nawa M, Kurita M, Tokizawa M,Iwamatsu A, Matsuoka M
    • Journal Title

      Cell Death Dis

      Volume: 4 Issue: 3 Pages: 555-555

    • DOI

      10.1038/cddis.2013.80

    • Related Report
      2012 Annual Research Report 2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] MOCA is an integrator of the neuronal death signals that are activated by familial Alzheimer 's disease-related mutants of amyloid beta precursor protein and presenilin2012

    • Author(s)
      Tachi N, Hashimoto Y, Matsuoka M
    • Journal Title

      Biochem. J

      Volume: 442 Issue: 2 Pages: 413-422

    • DOI

      10.1042/bj20100993

    • Related Report
      2012 Annual Research Report 2012 Final Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Caricasole AVSTM2L is a novel secreted antagonist of the neuroprotective peptide Humanin2011

    • Author(s)
      Rossini L, Hashimoto Y, Suzuki H, Kurita M, Gianfriddo M, Scali C, Roncarati R, Franceschini D, Pollio G, Trabalzini L, Terstappen GC, Matsuoka M
    • Journal Title

      FASEB J.

      Volume: 25 Issue: 6 Pages: 1983-2000

    • DOI

      10.1096/fj.10-163535

    • Related Report
      2012 Final Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] VSTM2L is a novel secreted antagonist of the neuroprotective peptide Humanin2011

    • Author(s)
      Rossini, L, Hashimoto, Y., et al
    • Journal Title

      FASEB Journal

      Volume: 25(In press)

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TAG-1 in an inhibitor of TGFβ2-induced neuronal cell death via amyloid β precursor protein2010

    • Author(s)
      Tachi, N., Hashimoto, Y., et al
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 394 Pages: 119-125

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Humanin and the receptors for Humanin2010

    • Author(s)
      Matsuoka, M., Hashimoto, Y.
    • Journal Title

      Molecular Neurobiology

      Volume: 41 Pages: 22-28

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Presentation] SH3BP5 is essential for Humanin-mediated protection against Alzheimer's disease-relevant toxicity2013

    • Author(s)
      竹下裕二、橋本祐一、内野博之、松岡正明
    • Organizer
      日本薬理学会第86回大会
    • Place of Presentation
      福岡国際会議場
    • Year and Date
      2013-03-23
    • Related Report
      2012 Final Research Report
  • [Presentation] Involvement of MOCA in Alzheimer ' s disease-relevant neuronal cell death via APP and presenilins2011

    • Author(s)
      Hashimoto Y, Tachi N, Matsuoka M
    • Organizer
      Society for Neuroscience 2011 Annual Meeting
    • Place of Presentation
      ワシントン D.C
    • Year and Date
      2011-11-12
    • Related Report
      2012 Final Research Report
  • [Presentation] Involvement of MOCA in Alzheimer's disease-relevant neuronal cell death via APP and presenilins2011

    • Author(s)
      Yuichi Hashimoto
    • Organizer
      Society for Neuroscience 2011 Annual Meeting
    • Place of Presentation
      米国ワシントンD.C.
    • Year and Date
      2011-11-12
    • Related Report
      2011 Annual Research Report
  • [Presentation] Involvement of MOCA in neuronal cell death triggered by familial Alzheimer's disease-linked mutants of APP and presenilins.2011

    • Author(s)
      橋本祐一、太知信之、名和幹朗、松岡正明
    • Organizer
      日本薬理学会 第84回大会
    • Place of Presentation
      横浜
    • Year and Date
      2011-03-16
    • Related Report
      2012 Final Research Report
  • [Presentation] Involvement of MOCA in neuronal cell death triggered by familial Alzheimer's disease-linked mutants of APP and presenilins2011

    • Author(s)
      Hashimoto, Y., et al.
    • Organizer
      第84回日本薬理学会
    • Place of Presentation
      横浜
    • Year and Date
      2011-03-16
    • Related Report
      2010 Annual Research Report
  • [Presentation] SH3BP5 is essential for Humanin-mediated protection against Alzheimer’s disease-relevant toxicity

    • Author(s)
      Yuji Takeshita
    • Organizer
      第86回日本薬理学会年会
    • Place of Presentation
      福岡国際会議場
    • Related Report
      2012 Annual Research Report
  • [Remarks]

    • URL

      http://www.tokyo-med.ac.jp/pharmacol/top.html

    • Related Report
      2012 Final Research Report
  • [Remarks]

    • URL

      http://www.tokyo-med.ac.jp/pharmacol/top.html

    • Related Report
      2010 Annual Research Report

URL: 

Published: 2010-08-23   Modified: 2019-07-29  

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