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Development of a novel gene therapy on narcolepsy using AAV vectors and artificial GPCRs

Research Project

Project/Area Number 23659134
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field General pharmacology
Research InstitutionKanazawa University

Principal Investigator

MIEDA Michihiro  金沢大学, 医学系, 准教授 (20296552)

Co-Investigator(Renkei-kenkyūsha) SAKURAI Takeshi  金沢大学, 医学系, 教授 (60251055)
Project Period (FY) 2011 – 2013
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
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)
Keywords中枢・末梢神経 / 睡眠・覚醒 / オレキシン / ノルアドレナリン / セロトニン / ウィルスベクター / DREADD / マウス / ナルコレプシー / AAV / 遺伝子治療 / 睡眠・覚醒
Research Abstract

The loss of orexin neurons in humans is associated with narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and cataplexy. However, the precise neural mechanisms downstream of orexin neurons remain unknown.
We found that the locus coeruleus noradrenergic and dorsal raphe serotonergic neurons play differential roles in the regulation of sleep/wakefulness by orexin neurons: the former stabilizes wakefulness episodes (reduce sleepiness) and the latter suppresses cataplexy in mice. In addition, we developed a system to suppress narcolepsy in mice by artificially activating these neurons using recombinant AAV vectors and an artificial GPCR called DREADD.

Report

(4 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Research-status Report
  • 2011 Research-status Report
  • Research Products

    (32 results)

All 2014 2013 2012 2011 Other

All Journal Article (13 results) (of which Peer Reviewed: 13 results,  Open Access: 1 results) Presentation (14 results) (of which Invited: 1 results) Remarks (5 results)

  • [Journal Article] Orexin neurons suppress narcolepsy via 2 distinct efferent pa thways.2014

    • Author(s)
      Hasegawa E, Yanagisawa M, Sakurai T, Mieda M.
    • Journal Title

      J Clin Invest.

      Volume: 124 Issue: 2 Pages: 604-16

    • DOI

      10.1172/jci71017

    • Related Report
      2013 Annual Research Report 2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] GABAergic neurons in the preoptic area send direct inhibitory projections to orexin neurons.2013

    • Author(s)
      Saito YC, Tsujino N, Hasegawa E, Akashi K, Abe M, Mieda M, Sakimura K, Sakurai T.
    • Journal Title

      Front Neural Circuits.

      Volume: 7 Pages: 192-192

    • DOI

      10.3389/fncir.2013.00192

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Orexin receptor-1 in the locus coeruleus plays an important role in cue- dependent fear memory consolidation.2013

    • Author(s)
      Soya S, Shoji H, Hasegawa E, Hondo M, Miyakawa T, Yanagisawa M, Mieda M, Sakurai T.
    • Journal Title

      J Neurosci.

      Volume: 33 Issue: 36 Pages: 14549-57

    • DOI

      10.1523/jneurosci.1130-13.2013

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Differential roles of orexin receptors in the regulation of sleep/wakefulness2013

    • Author(s)
      Mieda M, Tsujino N, Sakurai T.
    • Journal Title

      Front Endocrinol

      Volume: 4 Pages: 57-57

    • DOI

      10.3389/fendo.2013.00057

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Neurotensin co-expressed in orexin-producing neurons in the lateral hypothalamus plays an important role in regulation of sleep/wakefulness States.2013

    • Author(s)
      Furutani N, Hondo M, Kageyama H, Tsujino N, Mieda M, Yanagisawa M, Shioda S, Sakurai T.
    • Journal Title

      PLoS One

      Volume: 8 Issue: 4 Pages: e62391-e62391

    • DOI

      10.1371/journal.pone.0062391

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Neurotensin co-expressed in orexin-producing neurons in the lateral hypothalamus plays an important role in regulation of sleep/wakefulness states2013

    • Author(s)
      Furutani. N
    • Journal Title

      PLoS one

      Volume: 印刷中

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Orexin (hypocretin) receptor agonists and antagonists for treatment of sleep disorders. Rationale for development and current status.2013

    • Author(s)
      Mieda. M
    • Journal Title

      CNS Drugs

      Volume: 27 Issue: 2 Pages: 83-90

    • DOI

      10.1007/s40263-012-0036-8

    • NAID

      120005254048

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Clock genes influence gene expression in growth plate and endochondral ossification in mice2012

    • Author(s)
      Takeshi Takarada, Ayumi Kodama, Shogo Hotta, Michihiro Mieda, Shigeki Shimba, Eiichi Hinoi and Yukio Yoneda
    • Journal Title

      J. Biol.Chem

      Volume: 287 Issue: 43 Pages: 36081-36095

    • DOI

      10.1074/jbc.m112.408963

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Overview of orexin/hypocretin system.2012

    • Author(s)
      Mieda. M
    • Journal Title

      Prog Brain Res

      Volume: 198 Pages: 5-14

    • DOI

      10.1016/b978-0-444-59489-1.00002-1

    • NAID

      120004419378

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Bmall in the nervous system is essential for normal adaptation of circadian locomotor activity and food intake to periodic feeding2011

    • Author(s)
      Mieda. M
    • Journal Title

      J.Neurosci.

      Volume: 31 Issue: 43 Pages: 15391-6

    • DOI

      10.1523/jneurosci.2801-11.2011

    • Related Report
      2013 Final Research Report 2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Pharmacogenetic modulation of orexin neurons alters sleep/wakefulness states in mice2011

    • Author(s)
      Sasaki. K
    • Journal Title

      PLoS One

      Volume: 6 Issue: 5 Pages: e20360-e20360

    • DOI

      10.1371/journal.pone.0020360

    • Related Report
      2013 Final Research Report 2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Differential roles of orexin receptor-1 and -2 in the regulation of non-REM and REM sleep2011

    • Author(s)
      Mieda. M
    • Journal Title

      J.Neurosci.

      Volume: 31 Issue: 17 Pages: 6518-26

    • DOI

      10.1523/jneurosci.6506-10.2011

    • NAID

      120003141604

    • Related Report
      2013 Final Research Report 2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Connectomics of orexin-producing neurons : interface of systems of emotion, energy homeostasis and arousal2011

    • Author(s)
      Sakurai. T
    • Journal Title

      Trends Pharmacol

      Volume: 32 Issue: 8 Pages: 451-62

    • DOI

      10.1016/j.tips.2011.03.007

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Presentation] Orexin neurons suppress narcolepsy via 2 distinct efferent pathways. Gordon Research Conferences2014

    • Author(s)
      Hasegawa, E., Yanagisawa, M., Sakurai, T., and Mieda, M
    • Organizer
      leep Regulation & Function
    • Place of Presentation
      Galveston, USA
    • Year and Date
      2014-05-17
    • Related Report
      2013 Final Research Report
  • [Presentation] Orexin neurons suppress narcolepsy via 2 distinct efferent pathways2014

    • Author(s)
      Hasegawa, E. Yanagisawa, M. Sakurai, T Mieda, M.
    • Organizer
      Gordon Research Conferences, Sleep Regulation & Function
    • Place of Presentation
      Galveston, TX, USA
    • Related Report
      2013 Annual Research Report
  • [Presentation] Restoration of orexin signaling in the dorsal raphe and locus coeruleus differentially ameliorate symptoms of narcoleptic mice2013

    • Author(s)
      Hasegawa, E., Yanagisawa, M., Roth, B.L., Sakurai, T., and Mieda, M
    • Organizer
      The 5th World Congress on Sleep Medicine
    • Place of Presentation
      Valencia, Spain
    • Year and Date
      2013-09-28
    • Related Report
      2013 Final Research Report
  • [Presentation] Restoration of orexin signaling in the dorsal raphe and locus coeruleus differentially ameliorate symptoms of narcoleptic mice2013

    • Author(s)
      Hasegawa, E. Yanagisawa, M. Roth, B.L Sakurai, T Mieda, M.
    • Organizer
      The 5th World Congress on Sleep Medicine
    • Place of Presentation
      Palacio de Congresos (Spain)
    • Related Report
      2013 Annual Research Report
  • [Presentation] Differential regulation of non-REM and REM sleep by orexinergic neurons2012

    • Author(s)
      Mieda, M
    • Organizer
      Neuroscience 2012, the 33th annual meeting of the Society for Neuroscience
    • Place of Presentation
      New Orleans, USA
    • Year and Date
      2012-10-17
    • Related Report
      2013 Final Research Report
  • [Presentation] Search for neurons mediating functions of orexin as a wakefulness-stabilizer2012

    • Author(s)
      Hasegawa, E., Yanagisawa, M., Sakurai, T., and Mieda, M
    • Organizer
      21st Congress of the European Sleep Research Society
    • Place of Presentation
      Paris, France
    • Year and Date
      2012-09-07
    • Related Report
      2013 Final Research Report
  • [Presentation] Search for neurons mediating functions of orexin as a wakefulness-stabilizer2012

    • Author(s)
      長谷川 恵美
    • Organizer
      日本生理学会
    • Place of Presentation
      松本文化会館(長野県)
    • Related Report
      2011 Research-status Report
  • [Presentation] Differential roles of orexin receptor-1 and -2 in the regulation of non-REM and REM sleep2011

    • Author(s)
      Mieda, M., Hasegawa, E., Kisanuki, Y.Y., Sinton, C.M., Yanagisawa, M., and Sakurai, T
    • Organizer
      Worldsleep2011 (World Federation of Sleep Research & Sleep Medicine Societies)
    • Place of Presentation
      Kyoto
    • Related Report
      2013 Final Research Report
  • [Presentation] Differential roles of orexin receptor-1 and -2 in the regulation of non-REM and REM sleep2011

    • Author(s)
      三枝 理博
    • Organizer
      World Sleep 2011
    • Place of Presentation
      京都国際会館(京都府)
    • Related Report
      2011 Research-status Report
  • [Presentation] オレキシン神経は、2つの異なる経路を介して覚醒状態を強化しカタプレキシーを抑制する

    • Author(s)
      長谷川恵美、柳沢正史、櫻井武、三枝理博
    • Organizer
      第36回日本神経科学会大会
    • Place of Presentation
      京都国際会議場(京都府)
    • Related Report
      2013 Annual Research Report
  • [Presentation] Differential regulation of non-REM and REM sleep by orexinergic neurons

    • Author(s)
      Mieda. M
    • Organizer
      Neuroscience 2012
    • Place of Presentation
      Morial Convention Center (USA)
    • Related Report
      2012 Research-status Report
    • Invited
  • [Presentation] Search for neurons mediating functions of orexin as a wakefulness-stabilizer

    • Author(s)
      Hasegawa. E
    • Organizer
      21st Congress of the European Sleep Research Society
    • Place of Presentation
      CNIT Paris La Défense(フランス)
    • Related Report
      2012 Research-status Report
  • [Presentation] 覚醒安定装置・オレキシンニューロンの機能を担う下流ニューロンの探索

    • Author(s)
      長谷川 恵美
    • Organizer
      第35回日本神経科学大会
    • Place of Presentation
      名古屋国際会議場(愛知県)
    • Related Report
      2012 Research-status Report
  • [Presentation] ナルコレプシーマウスにおいて、オレキシンニューロンは2つの異なる経路を介して覚醒分断化とカタプレキシーを抑制する

    • Author(s)
      長谷川 恵美
    • Organizer
      第90回日本生理学会大会
    • Place of Presentation
      タワーホール船堀(東京都)
    • Related Report
      2012 Research-status Report
  • [Remarks] 北國, 毎日, 北陸中日新聞(朝刊)平成26年1月3, 5日

    • URL

      http://www.kanazawa-u.ac.jp/university/administration/prstrategy/release/pdf/14/140103.pdf

    • Related Report
      2013 Final Research Report
  • [Remarks]

    • URL

      http://physiology.jp/exec/page/stopics89/

    • Related Report
      2013 Final Research Report
  • [Remarks]

    • URL

      http://www.jnss.org/140228-07/

    • Related Report
      2013 Final Research Report
  • [Remarks]

    • URL

      http://news.mynavi.jp/news/2014/01/10/347/

    • Related Report
      2013 Final Research Report
  • [Remarks] 突然眠り込むことの無いように脳を制御している 二つの神経メカニズムを解明

    • URL

      http://www.kanazawa-u.ac.jp/university/administration/prstrategy/release/pdf/14/140103.pdf

    • Related Report
      2013 Annual Research Report

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Published: 2011-08-05   Modified: 2019-07-29  

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