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新規睡眠制御遺伝子Sleepyの機能解析による睡眠覚醒制御の分子・神経基盤の解明

Research Project

Project/Area Number 15J06369
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section国内
Research Field Animal physiology/Animal behavior
Research InstitutionUniversity of Tsukuba

Principal Investigator

本多 隆利  筑波大学, グローバル教育院, 特別研究員(DC1)

Project Period (FY) 2015-04-24 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2017: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2016: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2015: ¥1,200,000 (Direct Cost: ¥1,200,000)
Keywords睡眠 / 覚醒 / フォワード・ジェネティクス(順遺伝学) / ホメオスタシス(恒常性) / 睡眠負債 / 網羅的行動テストバッテリー / フォワード・ジェネティクス
Outline of Annual Research Achievements

「眠気」の脳内での物理的実体や、日々の睡眠量を一定に保つ根本原理は未知である。当研究室ではフォワード・ジェネティクス研究により、睡眠過多を呈するSleepy変異マウス家系とその原因遺伝子Sik3を見出した。SIK3 はリン酸化酵素で、中央部にプロテインキナーゼA(PKA)認識部位があり、551番目のセリン(S551)により規定される。Sleepy変異家系は、S551を含む13番目のエクソンを欠損していた。そこで申請者は、進化的に保存されたPKA認識部位S551と睡眠覚醒制御の関係性を検証すべく、CRISPR法によりS551に点変異を導入し、S551A家系、S551D家系を作製、脳波・筋電図解析を行なった。その結果、両家系ともに同腹の野生型マウスに比べ、24時間を通じて顕著な覚醒時間の減少、ノンレム睡眠時間の増加がみられた。脳波スペクトラム解析の結果、睡眠要求量を評価する指標であるノンレム睡眠時の徐波(デルタ波)量が顕著に増加していた。分子レベルでは、培養細胞を用いた生化学解析の結果、SIK3 S551の変異・欠損により、リン酸化型PKAからの認識が減少し、蛋白質の局在や相互作用を司る14-3-3との結合が失われていた。この結果はPKA/SIK3/14-3-3を介した適切なシグナル伝達が正常な睡眠覚醒制御に不可欠であることを示唆する。本研究は、細胞内シグナル伝達系と個体レベルのダイナミックな睡眠覚醒行動を繋ぐ成果であり、単一遺伝子Sik3の単一アミノ酸S551が1日の睡眠量や睡眠要求量・眠気を規定する上で重要な役割を担うことを示した。また、当初の計画より更に発展した研究として、申請者は順遺伝学により同定した新規睡眠異常マウス家系に対し独自に網羅的行動テストバッテリーを構築・実施し新規表現型を明らかにした。今後は分子遺伝学や電気生理学等を組み合わせ、分子神経基盤の解明を進める。

Research Progress Status

平成29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成29年度が最終年度であるため、記入しない。

Report

(4 results)
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Products Report
  • Research Products

    (33 results)

All 2018 2017 2016 2015 Other

All Int'l Joint Research (1 results) Journal Article (6 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 6 results,  Open Access: 6 results,  Acknowledgement Compliant: 3 results) Presentation (25 results) (of which Int'l Joint Research: 15 results,  Invited: 8 results) Book (1 results)

  • [Int'l Joint Research] テキサス大学サウスウェスタン(UTSW)医学センター/マサチューセッツ工科大学(MIT)(米国)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] A single phosphorylation site of SIK3 regulates daily sleep amounts and sleep need in mice2018

    • Author(s)
      Honda Takato、Fujiyama Tomoyuki、Miyoshi Chika、Ikkyu Aya、Hotta-Hirashima Noriko、Kanno Satomi、Mizuno Seiya、Sugiyama Fumihiro、Takahashi Satoru、Funato Hiromasa、Yanagisawa Masashi
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 115 Issue: 41 Pages: 10458-10463

    • DOI

      10.1073/pnas.1810823115

    • Related Report
      Products Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Sleep/Wake Behaviors in Mice During Pregnancy and Pregnancy-Associated Hypertensive Mice2017

    • Author(s)
      Komiya Haruna、Miyoshi Chika、Iwasaki Kanako、Hotta-Hirashima Noriko、Ikkyu Aya、Kanno Satomi、Honda Takato、Gosho Masahiko、Hamada Hiromi、Satoh Toyomi、Fukamizu Akiyoshi、Funato Hiromasa、Yanagisawa Masashi
    • Journal Title

      Sleep

      Volume: 41 Issue: 3 Pages: 1-1

    • DOI

      10.1093/sleep/zsx209

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genetic interaction of DISC1 and Neurexin in the development of fruit fly glutamatergic synapses2017

    • Author(s)
      Pandey Himani、Bourahmoune Katia、Honda Takato、Honjo Ken、Kurita Kazuki、Sato Tomohito、Sawa Akira、Furukubo-Tokunaga Katsuo
    • Journal Title

      npj Schizophrenia

      Volume: 3 Issue: 1 Pages: 1-11

    • DOI

      10.1038/s41537-017-0040-6

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Forward-genetics analysis of sleep in randomly mutagenized mice2016

    • Author(s)
      Funato H and Yanagisawa M et al.
    • Journal Title

      Nature

      Volume: 539(7629) Issue: 46 Pages: 378-383

    • DOI

      10.1038/nature20142

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Identification of mutations through dominant screening for obesity using C57BL/6 substrains2016

    • Author(s)
      Hossain MS., Funato H, and Yanagisawa M et al.
    • Journal Title

      Scientific Reports

      Volume: 6 Issue: 1 Pages: 32453-32453

    • DOI

      10.1038/srep32453

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Artificial Induction of Associative Olfactory Memory by Optogenetic and Thermogenetic Activation of Olfactory Sensory Neurons and Octopaminergic Neurons in Drosophila Larvae2016

    • Author(s)
      Takato Honda *, Chi-Yu Lee, Ken Honjo, Katsuo Furukubo-Tokunaga * (* Corresponding Author)
    • Journal Title

      Frontiers in Behavioral Neuroscience

      Volume: 10

    • DOI

      10.3389/fnbeh.2016.00137

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] フォワード・ジェネティクスにより同定した新規睡眠覚醒制御遺伝子 Sik3 の睡眠覚醒制御基盤の解析2018

    • Author(s)
      本多 隆利, 藤山 知之, 三好 千香, 船戸 弘正, 柳沢 正史
    • Organizer
      第41回 日本神経科学学会 (The 41st Annual Meeting of the Japan Neuroscience Society), 神戸コンベンションセンター [演題採択済]
    • Related Report
      2017 Annual Research Report
  • [Presentation] フォワード・ジェネティクスにより同定した新規睡眠覚醒制御遺伝子 Sik3 の睡眠覚醒制御基盤の解析2018

    • Author(s)
      本多 隆利, 藤山 知之, 三好 千香, 船戸 弘正, 柳沢 正史
    • Organizer
      第43回 日本睡眠学会 定期学術集会 (The 43rd Japanese Society of Sleep Research):第9回 アジア睡眠学会 / アジア時間生物学フォーラム 2018 合同開催), 札幌コンベンションセンター [演題採択済]
    • Related Report
      2017 Annual Research Report
  • [Presentation] Investigation of Sleep/Wake Regulatory Mechanisms by Analysis of the Sik3 Gene Identified Through Forward Genetics2018

    • Author(s)
      Takato Honda, Tomoyuki Fujiyama, Chika Miyoshi, Hiromasa Funato, Masashi Yanagisawa
    • Organizer
      The 68th Lindau Nobel Laureate Meeting, Lindau, Germany [演題採択済] [Travel Award]
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Neural Circuit and Molecular Basis of Behavioral Phenotypes in Mouse Pedigrees with Sleep Abnormalities Identified through Forward Genetics2017

    • Author(s)
      本多 隆利, 藤山 知之, 三好 千香, 船戸 弘正, 柳沢 正史
    • Organizer
      2017年度 生命科学系学会合同年次大会 (ConBio 2017) : 第40回日本分子生物学会年会 / 第90回日本生化学会大会 合同開催, 神戸コンベンションセンター
    • Related Report
      2017 Annual Research Report
  • [Presentation] Investigation of Sleep/Wake Regulatory Mechanisms by Analysis of the Sik3 Gene Identified Through Forward Genetics2017

    • Author(s)
      Takato Honda, Tomoyuki Fujiyama, Chika Miyoshi, Hiromasa Funato, Masashi Yanagisawa
    • Organizer
      The 6th Annual IIIS Symposium - Solving the Mystery of Sleep -, 東京コンファレンスセンター
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] フォワード・ジェネティクスにより樹立された睡眠異常マウス家系の行動表現型における分子・神経回路基盤2017

    • Author(s)
      本多 隆利, 藤山 知之, 三好 千香, 船戸 弘正, 柳沢 正史
    • Organizer
      第40回 日本神経科学学会 (The 40th Annual Meeting of the Japan Neuroscience Society), 幕張メッセ
    • Related Report
      2017 Annual Research Report
  • [Presentation] 脳神経科学の最前線:『睡眠』の制御メカニズムの解明に挑む2017

    • Author(s)
      本多 隆利
    • Organizer
      茨城県立水海道第一高等学校 ブライトスター計画事業, 筑波大学 国際統合睡眠医科学研究機構(WPI-IIIS)
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Systematic Behavioral Screening for Sleepy and Dreamless, Newly Identified Mouse Pedigrees with Sleep Abnormalities2016

    • Author(s)
      Takato Honda, Tomoyuki Fujiyama, Chika Miyoshi, Hiromasa Funato, Masashi Yanagisawa
    • Organizer
      Society for Neuroscience (SfN) : Neuroscience 2016
    • Place of Presentation
      San Diego Convention Center, San Diego, CA, USA
    • Year and Date
      2016-11-12
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 光と熱で神経回路を活性化 生きた昆虫の脳に人工的な記憶の形成に成功 - 光遺伝学・熱遺伝学を用いた連合学習パラダイムの開発 -2016

    • Author(s)
      本多 隆利, 古久保-徳永 克男
    • Organizer
      第56回 生化学若い研究者の会 (The 56th Young Researchers Society for Biochemistry):生命科学夏の学校2016 [最優秀発表賞(Best Presentation Award)受賞]
    • Place of Presentation
      旅館かつらや, 宮城県, 白石市
    • Year and Date
      2016-08-26
    • Related Report
      2016 Annual Research Report
  • [Presentation] フォワード・ジェネティクスにより樹立された新規睡眠異常マウス家系 Sleepy・Dreamless の網羅的行動解析2016

    • Author(s)
      本多 隆利, 藤山 知之, 三好 千香, 船戸 弘正, 柳沢 正史
    • Organizer
      第39回 日本神経科学学会(The 39th Annual Meeting of the Japan Neuroscience Society)
    • Place of Presentation
      パシフィコ横浜, 神奈川県, 横浜市
    • Year and Date
      2016-07-20
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Systematic Behavioral Screening of Sleepy and Dreamless, Newly Identified Mouse Pedigrees with Sleep Abnormalities2016

    • Author(s)
      本多 隆利, 藤山 知之, 三好 千香, 船戸 弘正, 柳沢 正史
    • Organizer
      第41回 日本睡眠学会 定期学術集会(The 41st Annual Meeting of the Japanese Society of Sleep Research) [フォーカスドシンポジウム採択演題]
    • Place of Presentation
      京王プラザホテル, 東京都, 新宿区
    • Year and Date
      2016-07-07
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 脳・神経科学の最前線:遺伝子と神経回路で紐解く動物行動のしくみ2016

    • Author(s)
      本多 隆利
    • Organizer
      長崎県立長崎西高等学校 スーパー・サイエンス・ハイスクール(SSH)事業 特別講義
    • Place of Presentation
      長崎県立長崎西高等学校
    • Year and Date
      2016-03-09
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Systematic Behavioral Screening of Sleepy and Dreamless, Newly Identified Mouse Pedigrees with Sleep Abnormalities2016

    • Author(s)
      Takato Honda, Tomoyuki Fujiyama, Chika Miyoshi, Makito Sato, Hiromasa Funato and Masashi Yanagisawa
    • Organizer
      The 4th Annual IIIS Symposium - Solving the Mystery of Sleep -
    • Place of Presentation
      International Institute for Integrative Sleep Medicine (WPI-IIIS), Tsukuba, Japan
    • Year and Date
      2016-02-26
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 現代神経科学の謎:『睡眠』の制御メカニズムに挑む2016

    • Author(s)
      本多 隆利
    • Organizer
      第97回 科学・技術産業イニシアティブ
    • Place of Presentation
      文部科学省 研究交流センター
    • Year and Date
      2016-02-26
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] フォワード・ジェネティクスにより樹立された新規睡眠異常家系マウスの網羅的行動解析2016

    • Author(s)
      本多 隆利, 藤山 知之, 三好 千香, 佐藤 牧人, 船戸 弘正, 柳沢 正史
    • Organizer
      SAT テクノロジー・ショーケース 2016(ベストプレゼンテーション賞:若手奨励賞 受賞)
    • Place of Presentation
      つくば国際会議場
    • Year and Date
      2016-02-04
    • Related Report
      2015 Annual Research Report
  • [Presentation] n vivo Genetic Verification of Sleepy Mutation & Systematic Behavioral Screening for Forward-genetically Identified Mouse Pedigrees with Sleep Abnormalities2016

    • Author(s)
      Takato Honda, Tomoyuki Fujiyama, Chika Miyoshi, Hiromasa Funato, Masashi Yanagisawa
    • Organizer
      Seminar at The Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT)
    • Place of Presentation
      The Picower Institute for Learning and Memory, Massachusetts Institute of Technology (MIT), Cambridge, MA, USA
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Systematic Behavioral Screening for Sleepy and Dreamless, Newly Identified Mouse Pedigrees with Sleep Abnormalities2016

    • Author(s)
      Takato Honda, Tomoyuki Fujiyama, Chika Miyoshi, Hiromasa Funato, Masashi Yanagisawa
    • Organizer
      The Sleep and Circadian Neurobiology Society
    • Place of Presentation
      Hilton San Diego Bayfront, San Diego, CA, USA
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 脳・神経科学の最前線:現代神経科学の謎 『睡眠』の制御メカニズムの解明に挑む2016

    • Author(s)
      本多 隆利
    • Organizer
      茨城県立水海道第一高等学校 ブライトスター計画事業
    • Place of Presentation
      筑波大学 国際統合睡眠医科学研究機構(WPI-IIIS), 茨城県, つくば市
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Systematic Behavioral Screen for Newly Identified Mouse Pedigrees with Sleep Abnormalities2016

    • Author(s)
      Takato Honda, Tomoyuki Fujiyama, Chika Miyoshi, Hiromasa Funato, Masashi Yanagisawa
    • Organizer
      Interdisciplinary Workshop on Science and Patents (IWP) 2016 [IWP Prize : Distinguished Presentation Prize 受賞]
    • Place of Presentation
      University of Tsukuba, Tsukuba, Ibaraki, Japan
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Frontiers in Neuroscience - Molecular・Neural Circuit Basis of Animal Behaviors -2016

    • Author(s)
      Takato Honda
    • Organizer
      長崎県立長崎西高等学校 さくらサイエンスプラン 科学技術振興機構(JST)日本・アジア青少年サイエンス交流事業
    • Place of Presentation
      長崎県立長崎西高等学校, 長崎県, 長崎市
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Systematic Behavioral Test Battery for Sleepy and Dreamless, Newly Identified Mouse Pedigrees with Sleep Abnormalities2015

    • Author(s)
      Takato Honda, Tomoyuki Fujiyama, Chika Miyoshi, Makito Sato, Hiromasa Funato and Masashi Yanagisawa
    • Organizer
      Exploring Complex Systems : from Human Biology to Exercise Science
    • Place of Presentation
      University of California, Irvine (UCI), CA, USA
    • Year and Date
      2015-12-09
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Artificial Induction of Associative Olfactory Memory by Targeted Activation of the Memory Circuits in Drosophila Larvae2015

    • Author(s)
      Takato Honda, Chi-Yu Lee, Ken Honjo and Katsuo Furukubo-Tokunaga
    • Organizer
      The 7th International Symposium on Optogenetics - Neural Circuits and Neuromodulations-(Travel Award 受賞)
    • Place of Presentation
      Tokyo Medical and Dental University, Tokyo, Japan
    • Year and Date
      2015-11-04
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Systematic Behavioral Screening of Sleepy and Dreamless, Newly Identified Mouse Pedigrees with Sleep Abnormalities2015

    • Author(s)
      Takato Honda, Tomoyuki Fujiyama, Chika Miyoshi, Makito Sato, Hiromasa Funato and Masashi Yanagisawa
    • Organizer
      Tsukuba Global Science Week (TGSW) 2015(Best Speaker Award : 最優秀発表賞 受賞)
    • Place of Presentation
      Tsukuba International Conference Center EPOCAL Tsukuba, Tsukuba, Japan
    • Year and Date
      2015-09-28
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Systematic Behavioral Test Battery for the Newly Identified Mouse Pedigrees with Sleep Abnormalities2015

    • Author(s)
      Takato Honda, Tomoyuki Fujiyama, Chika Miyoshi, Makito Sato, Hiromasa Funato and Masashi Yanagisawa
    • Organizer
      The University of Edinburgh Summer School Symposium
    • Place of Presentation
      The University of Edinburgh, Edinburgh, Scotland, UK
    • Year and Date
      2015-09-21
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Artificial Induction of Associative Olfactory Memory by Targeted Activation of the Memory Circuits in Drosophila Larvae2015

    • Author(s)
      Takato Honda, Chi-Yu Lee, Ken Honjo and Katsuo Furukubo-Tokunaga
    • Organizer
      2015 Bridging Biomedical Worlds : From Neural Circuitry to Neurotechnology
    • Place of Presentation
      Iino Hall and Conference Center, Tokyo, Japan
    • Year and Date
      2015-05-11
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Book] 『"眠気"の実体を探る ─フォワード・ジェネティクスによる新規睡眠制御遺伝子の探索:Search for the Neuronal Substrate of "Sleepiness" - Forward Genetics for Identification of Novel Sleep/Wake Regulating Genes -』,「睡眠・覚醒制御機構研究の新展開」, 医学のあゆみ(Journal of Clinical and Experimental Medicine)2017

    • Author(s)
      本多 隆利(Takato Honda), 柳沢 正史(Masashi Yanagisawa)
    • Total Pages
      9
    • Publisher
      医歯薬出版
    • Related Report
      2017 Annual Research Report

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Published: 2015-11-26   Modified: 2024-03-26  

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