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Analysis of the role of ceramide kinase in dyslipidemia and its application to drug discovery

Research Project

Project/Area Number 17K08303
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pharmacology in pharmacy
Research InstitutionChiba University

Principal Investigator

Nakamura Hiroyuki  千葉大学, 大学院薬学研究院, 准教授 (20447311)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsセラミドキナーゼ / セラミド-1-リン酸 / 脂質代謝異常症 / グリア細胞 / 脱髄 / オートファジー
Outline of Final Research Achievements

The dyslipidemia focused in this study is an intractable disease in which cholesterol and sphingolipids accumulate in cells and cause central nervous system disorders (particularly, Purkinje cell loss). In this study, we analyzed the role of ceramide kinase in dyslipidemia using cell, mouse, disease-specific iPS cells. The results showed that inhibition of ceramide kinase suppressed the onset of dyslipidemia.

Academic Significance and Societal Importance of the Research Achievements

本研究で着目している脂質代謝異常症は遺伝病であるため、根本的な治療には遺伝子治療が必要である。しかしながら、遺伝子治療の実用化は容易ではない。本研究により脂質蓄積症の病態発症機構の一端が明らかになり、さらに、セラミドキナーゼが創薬標的となることが明らかになった。今後、新規セラミドキナーゼ阻害剤を開発することで、本病態の革新的治療薬を創出できる可能性がある。

Report

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

    (54 results)

All 2020 2019 2018 2017 Other

All Journal Article (10 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 10 results,  Open Access: 1 results) Presentation (38 results) (of which Int'l Joint Research: 8 results,  Invited: 2 results) Book (2 results) Remarks (1 results) Patent(Industrial Property Rights) (3 results) (of which Overseas: 2 results)

  • [Journal Article] Accumulation of sphingomyelin in Niemann-Pick disease type C cells disrupts Rab9-dependent vesicular trafficking of cholesterol2020

    • Author(s)
      Wanikawa M, Nakamura H, Emori S, Hashimoto N, Murayama T
    • Journal Title

      J Cell Physiol

      Volume: 235 Issue: 3 Pages: 2300-2309

    • DOI

      10.1002/jcp.29137

    • NAID

      130007811259

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibitory effects of ceramide kinase on Rac1 activation, lamellipodium formation, cell migration, and metastasis of A549 lung cancer cells2020

    • Author(s)
      Tomizawa S, Tamori M, Tanaka A, Utsumi N, Sato H, Hatakeyama H, Hisaka A, Kohama T, Yamagata K, Honda T, Nakamura H, Murayama T
    • Journal Title

      Biochim Biophys Acta Mol Cell Biol Lipids

      Volume: 1865 Issue: 6 Pages: 158675-158675

    • DOI

      10.1016/j.bbalip.2020.158675

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Down-regulation of ceramide kinase via proteasome and lysosome pathways in PC12 cells by serum withdrawal: Its protection by nerve growth factor and role in exocytosis2020

    • Author(s)
      Hori M, Gokita M, Yasue M, Honda T, Kohama T, Mashimo M, Nakamura H, Murayama T
    • Journal Title

      Biochim Biophys Acta Mol Cell Res

      Volume: in press Issue: 7 Pages: 118714-118714

    • DOI

      10.1016/j.bbamcr.2020.118714

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Phosphorylation and inhibition of ceramide kinase by protein kinase C-β: Their changes by serine residue mutations2019

    • Author(s)
      Takahashi H, Ashikawa H, Nakamura H, Murayama T
    • Journal Title

      Cell Signal

      Volume: 54 Pages: 59-68

    • DOI

      10.1016/j.cellsig.2018.11.008

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Translocation and activation of sphingosine kinase 1 by ceramide-1-phosphate2019

    • Author(s)
      Nishino S, Yamashita H, Tamori M, Mashimo M, Yamagata K, Nakamura H, Murayama T
    • Journal Title

      J Cell Biochem

      Volume: 120 Issue: 4 Pages: 5396-5408

    • DOI

      10.1002/jcb.27818

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Knockout of Ceramide Kinase Aggravates Pathological and Lethal Responses in Mice with Experimental Colitis2018

    • Author(s)
      Suzuki S, Tanaka A, Nakamura H, Murayama T
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 41 Issue: 5 Pages: 797-805

    • DOI

      10.1248/bpb.b18-00051

    • NAID

      130006730700

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2018-05-01
    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Development of a new doubly-labeled fluorescent ceramide probe for monitoring the metabolism of sphingolipids in living cells2018

    • Author(s)
      Wang Y, Kasahara J, Yamagata K, Nakamura H, Murayama T, Suzuki N, Nishida A
    • Journal Title

      Bioorg Med Chem Lett

      Volume: 28 Issue: 19 Pages: 3222-3226

    • DOI

      10.1016/j.bmcl.2018.08.013

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Cellular density-dependent increases in HIF-1α compete with c-Myc to down-regulate human EP4 receptor promoter activity through Sp-1-binding region2018

    • Author(s)
      Seira N, Yamagata K, Fukushima K, Araki Y, Kurata N, Yanagisawa N, Mashimo M, Nakamura H, Regan JW, Murayama T, Fujino H
    • Journal Title

      Pharmacol Res Perspect

      Volume: 6 Issue: 6

    • DOI

      10.1002/prp2.441

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Antifibrotic effects of cyclosporine A on TGF-β1-treated lung fibroblasts and lungs from bleomycin-treated mice: role of hypoxia-inducible factor-1α2017

    • Author(s)
      Yamazaki R, Kasuya Y, Fujita T, Umezawa H, Yanagihara M, Nakamura H, Yoshino I, Tatsumi K, Murayama T
    • Journal Title

      FASEB J.

      Volume: 31 Issue: 8 Pages: 3359-3371

    • DOI

      10.1096/fj.201601357r

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Lactosylceramide-Induced Phosphorylation Signaling to Group IVA Phospholipase A2 via Reactive Oxygen Species in Tumor Necrosis Factor-α-Treated Cells2017

    • Author(s)
      Nakamura H, Moriyama Y, Watanabe K, Tomizawa S, Yamazaki R, Takahashi H, Murayama T
    • Journal Title

      J. Cell. Biochem.

      Volume: 118 Issue: 12 Pages: 4370-4382

    • DOI

      10.1002/jcb.26091

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] ニーマン・ピック病C型におけるセラミドキナーゼの関与と治療標的としての検討2020

    • Author(s)
      内海直也, 橋本直宏, 中村浩之, 村山俊彦
    • Organizer
      日本薬学会第140年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 記憶形成におけるセラミドキナーゼの関与2020

    • Author(s)
      穴田幸平, 中村浩之, 村山俊彦
    • Organizer
      日本薬学会第140年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ニーマン・ピック病C型においてスフィンゴミエリンはRab9依存性の小胞輸送を抑制してコレステロール蓄積を誘導する2020

    • Author(s)
      中村浩之, 鰐川雅裕, 江森俊介, 橋本直宏, 村山俊彦
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] チロシンキナーゼSrcによるグルコシルセラミド産生亢進機構2020

    • Author(s)
      本田拓也, 元吉海星, 笠原潤也, 山形一行, 中村浩之, 村山俊彦
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Srcによるグルコシルセラミド合成酵素活性化機構の解明2019

    • Author(s)
      元吉 海星, 本田拓也, 笠原 潤也, 山形 一行, 中村 浩之, 村山 俊彦
    • Organizer
      第63回 日本薬学会関東支部大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ニーマン・ピック病C型の病態解明と創薬標的の探索2019

    • Author(s)
      中村浩之, 村山俊彦
    • Organizer
      生体機能と創薬シンポジウム2019
    • Related Report
      2019 Annual Research Report
  • [Presentation] 神経成長因子NGFを介したセラミドキナーゼによる神経伝達制御機構の解明2019

    • Author(s)
      安江 匡隆, 堀 真悠子, 五木田 緑, 本田 拓也, 中村 浩之, 村山 俊彦
    • Organizer
      第140回 日本薬理学会関東部会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ニーマン・ピック病C型の病態発症機構の解明2019

    • Author(s)
      中村浩之, 本田拓也, 村山俊彦
    • Organizer
      第18回生命科学研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 特発性肺線維症におけるTGF-β1 シグナルの解明2019

    • Author(s)
      岩田 眞優, 本田 拓也, 中村 浩之, 村山 俊彦
    • Organizer
      第3回下総薬理学研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] HIF-1α and c-Myc oppositely regulate human EP4 receptor promoter activity in human colon cancer HCA-7 cells2019

    • Author(s)
      山形 一行, 清良 尚史, 福島 圭穣, 荒木 裕美, 倉田 直希, 柳澤 直樹, 間下 雅士, 中村 浩之, REGAN W. John, 村山 俊彦, 藤野 裕道
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] セラミドキナーゼによるアクチン細胞骨格と細胞遊走制御機構の解明2019

    • Author(s)
      中村 浩之, 冨澤 智史, 村山 俊彦
    • Organizer
      第92回日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] セラミドキナーゼノックアウトマウスを用いた行動学的解析2019

    • Author(s)
      穴田 幸平, 中村 浩之, 村山 俊彦
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Research-status Report
  • [Presentation] Srcによるチロシンリン酸化を介したグルコシルセラミド合成酵素活性化2019

    • Author(s)
      本田 拓也, 笠原 潤也, 元吉 海星, 山形 一行, 中村 浩之, 村山 俊彦
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Research-status Report
  • [Presentation] リン酸化シグナルによるセラミドキナーゼ活性制御機構の解明2019

    • Author(s)
      中村 浩之, 芦川 仁美, 高橋 宏昌, 村山 俊彦
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Research-status Report
  • [Presentation] ニーマン・ピック病C型におけるセラミド-1-リン酸産生機構の解明2018

    • Author(s)
      橋本真美, 中村浩之, 村山俊彦
    • Organizer
      第2回下総薬理学研究会
    • Related Report
      2018 Research-status Report
  • [Presentation] ニーマン・ピック病C型におけるセラミドキナーゼの関与と病態制御機構の解明2018

    • Author(s)
      内海直也, 中村浩之, 村山俊彦
    • Organizer
      第2回下総薬理学研究会
    • Related Report
      2018 Research-status Report
  • [Presentation] The role of ceramide kinase in the pathophysiology of multiple sclerosis2018

    • Author(s)
      Tanaka A, Nakamura H, Murayama T
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology (WCP2018)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Sphingomyelin disrupts vesicular trafficking of cholesterol in Niemann-Pick disease type C2018

    • Author(s)
      Nakamura H, Wanikawa M, Emori S, Hashimoto N, Murayama T
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology (WCP2018)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] The involvement of ceramide kinase/ceramide-1-phosphate in NGF-induced differentiation and neurotransmission in PC12 cells2018

    • Author(s)
      Hori M, Gokita M, Nakamura H, Murayama T
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology (WCP2018)
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] ニーマン・ピック病C型の病態解明と創薬2018

    • Author(s)
      中村浩之
    • Organizer
      Open Discussion for Orphan Drug Discovery (ODOD 2018)
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Hypoxia inducible factor-1α regulates human EP4 receptor expression by binding to specificity protein-12018

    • Author(s)
      Seira N, Yamagata K, Fukushima K, Araki Y, Kurata N, Yanagisawa N, Mashimo M, Nakamura H, Regan J.W, Murayama T, Fujino H
    • Organizer
      The 3rd Joint Seminar between Faculty of Pharmacy, Mahidol University and Graduate School of Pharmaceutical Sciences, Chiba University
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Effects of antiepileptic drugs on Niemann-Pick disease type C2018

    • Author(s)
      Ashikawa H, Nakamura H, Murayama T
    • Organizer
      International Conference on the Bioscience of Lipids 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Role of ceramide kinase on lamellipodia formation and cell migration2018

    • Author(s)
      Nakamura H, Tomizawa S, Murayama T
    • Organizer
      International Conference on the Bioscience of Lipids 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] チロシンキナーゼ内在化型受容体であるEphA2のエンドサイトーシスにおけるセラミド-1-リン酸の役割2018

    • Author(s)
      田森 瑞貴, 成岡 詩織, 中村 浩之, 村山 俊彦
    • Organizer
      第3回トランスポーター研究会関東部会
    • Related Report
      2018 Research-status Report
  • [Presentation] セラミドキナーゼによる神経機能制御機構の解明2018

    • Author(s)
      五木田緑, 堀真悠子, 中村浩之, 村山俊彦
    • Organizer
      第138回日本薬理学会関東部会
    • Related Report
      2017 Research-status Report
  • [Presentation] 潰瘍性大腸炎におけるセラミドキナーゼの役割-ノックアウトマウスを用いた解析2018

    • Author(s)
      鈴木智美, 中村浩之, 村山俊彦
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] Srcによるグルコシルセラミド合成酵素活性化機構の解明2018

    • Author(s)
      笠原潤也, 山形一行, 中村浩之, 村山俊彦
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] TGFβ1線維化シグナルのスフィンゴ糖脂質による制御2017

    • Author(s)
      林今日太, 山崎璃沙, 中村浩之, 粕谷善俊, 村山俊彦
    • Organizer
      第1回下総薬理研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] ニーマン・ピック病C型における抗てんかん薬の有用性の検討2017

    • Author(s)
      芦川仁美, 中村浩之, 村山俊彦
    • Organizer
      第136回日本薬理学会関東部会
    • Related Report
      2017 Research-status Report
  • [Presentation] セラミド-1-リン酸によるEphA2動態制御機構の解明2017

    • Author(s)
      田森瑞貴, 成岡詩織, 中村浩之, 西野将平, 山下尚大, 村山俊彦
    • Organizer
      第136回日本薬理学会関東部会
    • Related Report
      2017 Research-status Report
  • [Presentation] ニーマン・ピック病C型における抗てんかん薬の有用性の検討2017

    • Author(s)
      芦川仁美, 中村浩之, 村山俊彦
    • Organizer
      生体機能と創薬シンポジウム2017
    • Related Report
      2017 Research-status Report
  • [Presentation] Effects of Antiepileptic drugs on Niemann-Pick disease type C2017

    • Author(s)
      芦川仁美, 中村浩之, 村山俊彦
    • Organizer
      次世代を担う創薬・医療薬理シンポジウム2017
    • Related Report
      2017 Research-status Report
  • [Presentation] セラミド-1-リン酸によるEphA2動態制御機構の解明2017

    • Author(s)
      田森瑞貴, 成岡詩織, 中村浩之, 西野将平, 山下尚大, 村山俊彦
    • Organizer
      次世代を担う創薬・医療薬理シンポジウム2017
    • Related Report
      2017 Research-status Report
  • [Presentation] Accumulation of sphingomyelin in Niemann-Pick disease type C disrupts vesicular trafficking of cholesterol2017

    • Author(s)
      Nakamura H, Wanikawa M, Emori S, Hashimoto N, Murayama T
    • Organizer
      International Conference on the Bioscience of Lipids 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Glucosylceramide synthase plays critical roles in TGF-β1-driven fibroblasts-myofibroblasts differentiation in human lung fibroblasts2017

    • Author(s)
      Yamazaki R, Watanabe K, Hayashi K, Nakamura H, Murayama T
    • Organizer
      International Conference on the Bioscience of Lipids 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] セラミド1-リン酸の生理機能と病態への関与2017

    • Author(s)
      中村浩之
    • Organizer
      セラミド研究会10周年記念大会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] セラミドキナーゼによるアクチン細胞骨格制御機構の解明2017

    • Author(s)
      冨澤智史, 中村浩之, 村山俊彦
    • Organizer
      セラミド研究会10周年記念大会
    • Related Report
      2017 Research-status Report
  • [Presentation] セラミド-1-リン酸によるEphA2動態制御機構の解明2017

    • Author(s)
      田森瑞貴, 中村浩之, 村山俊彦
    • Organizer
      セラミド研究会10周年記念大会
    • Related Report
      2017 Research-status Report
  • [Book] セラミド研究の新展開~基礎から応用へ~2019

    • Author(s)
      中村浩之
    • Total Pages
      337
    • Publisher
      株式会社 食品化学新聞社
    • ISBN
      9784916143358
    • Related Report
      2019 Annual Research Report
  • [Book] 脂質解析ハンドブック2019

    • Author(s)
      中村浩之、花田賢太郎
    • Total Pages
      310
    • Publisher
      羊土社
    • ISBN
      9784758122412
    • Related Report
      2019 Annual Research Report
  • [Remarks] 千葉大学大学院薬学研究院 薬効薬理学研究室

    • URL

      http://www.p.chiba-u.jp/lab/hinka/index

    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] Therapeutic agent for fibrosis and inhibitor of nuclear translocation of phosphorylated Smad2017

    • Inventor(s)
      中村浩之, 村山俊彦
    • Industrial Property Rights Holder
      千葉大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017
    • Acquisition Date
      2019
    • Related Report
      2019 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] 抗線維症剤およびリン酸化Smad核内移行阻害剤2017

    • Inventor(s)
      中村浩之, 村山俊彦
    • Industrial Property Rights Holder
      中村浩之, 村山俊彦
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2017-131587
    • Filing Date
      2017
    • Related Report
      2017 Research-status Report
  • [Patent(Industrial Property Rights)] THERAPEUTIC AGENT FOR FIBROSIS AND INHIBITOR OF NUCLEAR TRANSLOCATION OF PHOSPHORYLATED SMAD2017

    • Inventor(s)
      Nakamura H, Murayama T
    • Industrial Property Rights Holder
      Nakamura H, Murayama T
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017
    • Related Report
      2017 Research-status Report
    • Overseas

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Published: 2017-04-28   Modified: 2021-02-19  

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