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複数のシャルコー・マリー・トゥース病原因遺伝子に共通に関与するキー遺伝子の同定

Research Project

Project/Area Number 19K06659
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 44010:Cell biology-related
Research InstitutionKyoto Institute of Technology

Principal Investigator

山口 政光  京都工芸繊維大学, 応用生物学系, 教授 (00182460)

Co-Investigator(Kenkyū-buntansha) 吉田 英樹  京都工芸繊維大学, 応用生物学系, 准教授 (30570600)
Project Period (FY) 2019-04-01 – 2020-03-31
Project Status Discontinued (Fiscal Year 2019)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywordsシャルコー・マリー・トゥース病 / ショウジョウバエモデル / 長鎖非コードRNA / ヒストン脱アセチル化酵素 / FIG4遺伝子 / SLC25A46遺伝子 / 疾患モデルショウジョウバエ / Hippo遺伝子 / エピジェネティック制御遺伝子
Outline of Research at the Start

シャルコー・マリー・トゥース病(CMT)の原因遺伝子FIG4を標的とするCMTモデルショウジョウバエを用いた遺伝学的スクリーニングにより、表現型を抑圧するHippo遺伝子、長鎖非コードRNA(CR18854)遺伝子とエピジェネティック制御遺伝子gppを同定した。これらの遺伝子がCMTモデルショウジョウバエの示す表現型に寄与する仕組みを明らかにする。またこれらの遺伝子それぞれの突然変異が、他のCMT原因遺伝子を標的としたCMTモデルショウジョウバエが示す表現型を抑圧するか検討し、複数のCMT原因遺伝子に共通に関与する遺伝子を同定することで、これを標的とした新しい診断・治療法の開発に貢献する。

Outline of Annual Research Achievements

シャルコー・マリー・トゥース病(CMT)について多数の原因遺伝子が同定されているが、それらに共通に関与する遺伝子は、まだ同定されていない。それらの同定と機能解析は新しい診断・治療法の開発に有効である。申請者らは、これまでにCMT原因遺伝子FIG4を標的とするCMTモデルショウジョウバエを用いた遺伝学的スクリーニングを実施し、これらの表現型を抑圧する遺伝子としてHippo遺伝子、長鎖非コードRNAをコードするCR18854遺伝子とエピジェネティック制御遺伝子gpp等を同定していた。そこで本研究では、これらの遺伝子がCMTモデルショウジョウバエの表現型に寄与する仕組みについて明らかにし、また複数のCMT原因遺伝子に共通に関与する遺伝子を同定することを目的とした。
2019年度は、CR18854遺伝子をノックダウンしても、FIG4mRNAレベルは変化しないことが明らかになり、FIG4遺伝子はこの長鎖非コードRNAの直接の標的とはなっていないことがわかった。またさらに遺伝学的スクリーニングを進めた結果、他の長鎖非コードRNAをコードするCR43467遺伝子もFIG4遺伝子と遺伝学的相互作用することがわかった。興味深い事に、このCR43467遺伝子はdCOA7、dHADHBやdPDHBなどの他のCMT関連遺伝子と共通に遺伝学的相互作用することも明らかになった。これらの結果は、CMT病態の理解に長鎖非コードRNAに関する情報が不可欠であることを意味する。また他のCMT原因遺伝子SLC25A46とヒストン脱アセチル化酵素遺伝子Rpd3が遺伝学的相互作用することも見出した。Rpd3がヒストンH4K8のアセチル化レベルの制御を通じてSLC25A46の機能を抑制していることを明らかにした。これらの結果は、Rpd3阻害剤がCMT治療薬開発への鍵となることを示唆する。

Report

(1 results)
  • 2019 Annual Research Report
  • Research Products

    (32 results)

All 2020 2019 2018 Other

All Int'l Joint Research (6 results) Journal Article (14 results) (of which Int'l Joint Research: 9 results,  Peer Reviewed: 14 results,  Open Access: 6 results) Presentation (11 results) (of which Int'l Joint Research: 5 results,  Invited: 2 results) Remarks (1 results)

  • [Int'l Joint Research] チェンマイ大学(タイ)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] メキシコ自治大学(メキシコ)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] ダッカ大学(バングラデシュ)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] ケンブリッジ大学/ロンドン大学(英国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] タフツ大学(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research]

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Identification of CR43467 encoding a long non-coding RNA as a novel genetic interactant with dFIG4, a CMT-causing gene.2020

    • Author(s)
      Shimada, S., Muraoka, Y., Ibaraki, K., Takano-Shimizu-Kouno, T., Yoshida, H., and Yamaguchi, M.
    • Journal Title

      Experimental Cell Research

      Volume: 386 Issue: 1 Pages: 111711-111711

    • DOI

      10.1016/j.yexcr.2019.111711

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel genetic link between the ATP-binding cassette subfamily A gene and hippo gene in Drosophila.2020

    • Author(s)
      Ueoka I, Takai A, Chiyohobu T, Yoshida H and Yamaguchi M.
    • Journal Title

      Exp. Cell Res.

      Volume: 386 Issue: 2 Pages: 111733-111733

    • DOI

      10.1016/j.yexcr.2019.111733

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Neuron-specific knockdown of solute carrier protein SLC25A46a induces locomotive defects, an abnormal neuron terminal morphology, learning disability, and shortened lifespan.2020

    • Author(s)
      Ali, Md. S., Suda, K., Kowada, R., Ueoka, I., Yoshida, H., Yamaguchi, M.
    • Journal Title

      IBRO reports

      Volume: 8 Pages: 65-75

    • DOI

      10.1016/j.ibror.2020.02.001

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The DNA polymerases of Drosophila melanogaster.2020

    • Author(s)
      Marygold, S.J., Attrill, H., Speretta, E., Warner, K., Magrane, M., Orchard, S., Berloco, M., Cotterill, S., McVey, M., Rong, Y. and Yamaguchi, M.
    • Journal Title

      Fly (Austin)

      Volume: X Issue: 1-4 Pages: 1-13

    • DOI

      10.1080/19336934.2019.1710076

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] hDystrophin is required for normal synaptic gain in the Drosophila olfactory circuit.2019

    • Author(s)
      Jantrapirom, S., Cao, D., Wang, J., Hing, H., Tabone, C.J., Lantz, K., de Belle, J. S., Qiu, Y.T., Smid, H.M., Yamaguchi, M., Noordermeer, J.N., Fradkin, L.G., Potikanond, S.
    • Journal Title

      Brain Res.

      Volume: 1712 Pages: 158-166

    • DOI

      10.1016/j.brainres.2019.01.039

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Dystrobrevin is required postsynaptically for homeostatic potentiation at the Drosophila NMJ.2019

    • Author(s)
      Jantrapirom, S., Nimlamool, W., Temviriyanukul, P., Ahmadian, S., Locke, C.J., Davis, G.W., Yamaguchi, M.
    • Journal Title

      Biochim. Biophys. Acta

      Volume: 1865 Issue: 6 Pages: 1579-1591

    • DOI

      10.1016/j.bbadis.2019.03.008

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Neuron-specific knockdown of Drosophila HADHB induces a shortened lifespan, deficient locomotive ability, abnormal motor neuron terminal morphology and learning disability.2019

    • Author(s)
      Li J, Suda K, Ueoka I, Tanaka R, Yoshida H, Okada Y, Okamoto Y, Hiramatsu Y, Takashima H, Yamaguchi M.
    • Journal Title

      Exp. Cell Res.

      Volume: 379 Issue: 2 Pages: 150-158

    • DOI

      10.1016/j.yexcr.2019.03.040

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] The human Bcl-2 family member Bcl-rambo and voltage-dependent anion channels manifest a genetic interaction in Drosophila and cooperatively promote the activation of effector caspases in human cultured cells2019

    • Author(s)
      Hisanori Matsubara, Reiji Tanaka, Tatsuya Tateishi, Hideki Yoshida, Masamitsu Yamaguchi, Takao Kataoka
    • Journal Title

      Experimental Cell Research

      Volume: 381 Issue: 2 Pages: 223-234

    • DOI

      10.1016/j.yexcr.2019.05.015

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Drosophila Alpha-ketoglutarate-dependent dioxygenase AlkB is involved in repair from neuronal disorders induced by UV damage.2019

    • Author(s)
      Tsuji Wakisaka, K., Muraoka, Y., Shimizu, J., Yamaguchi, M., Ueoka, I., Mizuta, I., Yoshida, H. and Yamaguchi, M.
    • Journal Title

      NeuroReport

      Volume: 30 (15) Issue: 15 Pages: 1039-1047

    • DOI

      10.1097/wnr.0000000000001323

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Reduction of Rpd3 suppresses defects in locomotive ability and neuronal morphology induced by the knockdown of Drosophila SLC25A46 via an epigenetic pathway.2019

    • Author(s)
      Suda, K., Muraoka, Y., Ortega-Yanez, A., Yoshida, H., Kizu, F., Hochin, T., Kimura, H. and Yamaguchi, M.
    • Journal Title

      Exp Cell Res.

      Volume: 385 Issue: 2 Pages: 111673-111673

    • DOI

      10.1016/j.yexcr.2019.111673

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Cancer-related genes and ALS.2019

    • Author(s)
      Yamamoto, I., Azuma, Y. and Yamaguchi M.
    • Journal Title

      Front. Biosci.

      Volume: 24 Pages: 1242-1259

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Non-proteasomal UbL-UbA family of proteins in neurodegeneration.2019

    • Author(s)
      Jantrapirom, S., Lo Piccolo, L. and Yamaguchi M.
    • Journal Title

      Int. J. Mol. Sci.

      Volume: 20 Issue: 8 Pages: 1893-1893

    • DOI

      10.3390/ijms20081893

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Autism spectrum disorder-related syndromes: Modeling with Drosophila and rodents.2019

    • Author(s)
      Ueoka I., Pham H.T.N., Matsumoto K. and Yamaguchi M.
    • Journal Title

      Int. J. Mol. Sci.

      Volume: 20 (17) Issue: 17 Pages: 4071-4071

    • DOI

      10.3390/ijms20174071

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Novel roles of Drosophila FUS and Aub responsible for piRNA biogenesis in neuronal disorders.2018

    • Author(s)
      Wakisaka KT, Tanaka R, Hirashima T, Muraoka Y, Azuma Y, Yoshida H, Tokuda T, Asada S, Suda K, Ichiyanagi K, Ohno S, Itoh M, Yamaguchi M.
    • Journal Title

      Brain Res.

      Volume: 18 Pages: 30646-30652

    • DOI

      10.1016/j.brainres.2018.12.028

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Challenging the intractable neurological disorders such as ASD, ALS and CMT by Drosophila models2019

    • Author(s)
      Masamitsu Yamaguchi
    • Organizer
      International Symposium on Vietnamese traditional medicine for improvement of cognitive function
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Saudade of a retiring molecular biologist2019

    • Author(s)
      Masamitsu Yamaguchi
    • Organizer
      The 2nd Japan-Asean conference on Natural physiologically active substances by utilizing insect biomedical research
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Role of ATP-binding cassette subfamily C gene on the expression of neuropsychiatric disorders including autism by using Drosophila model2019

    • Author(s)
      Tran Quoc Dat, Vu Duc Anh, Nguyen Trong Tue, Hideki Yoshida, Masamitsu Yamaguchi
    • Organizer
      The 2nd Japan-Asean conference on Natural physiologically active substances by utilizing insect biomedical research
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Novel Drosophila model for Parkinson’s disease by targeting of phosphoglycerate kinase2019

    • Author(s)
      Joe Shimizu, Takashi Kasai, Hideki Yoshida, Masamitsu Yamaguchi
    • Organizer
      The 2nd Japan-Asean conference on Natural physiologically active substances by utilizing insect biomedical research
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] FIG4, a CMT-causing gene interacts with genes encoding long non-coding RNAs and epigenetic regulators2019

    • Author(s)
      Yuuka Muraoka, Aya Nakamura, Joe Shimizu, Hideki Yoshida, Masamitsu Yamaguchi
    • Organizer
      The 2nd Japan-Asean conference on Natural physiologically active substances by utilizing insect biomedical research
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] SCO2遺伝子を標的としたヒト希少神経難病Charcot-Marie-Tooth病の新規ショウジョウバエモデルの開発2019

    • Author(s)
      古和田凌佑、須田晃治郎、吉田英樹、山口政光
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Drosophila model as therapeutic target of mitochondrial disease2019

    • Author(s)
      Md Saheb Ali, Kojiro Suda, Hideki Yoshida, Masamitsu Yamaguchi
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] CMTの原因遺伝子FIG4と遺伝学的に相互作用するエピジェネティック制御遺伝子Rpd3の同定2019

    • Author(s)
      村岡夕香、吉田英樹、山口政光
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ショウジョウバエモデルを用いたリボソーム生合成障害による神経発達症の病態解析2019

    • Author(s)
      高井あかり、千代延友裕、上岡伊吹、山口瑞季、田中領、吉田英樹、山口政光
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] BCL11を標的としたショウジョウバエの新規神経発達症モデルの解析2019

    • Author(s)
      山口瑞季、高井あかり、千代延友裕、吉田英樹、山口政光
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] パーキンソン病新規原因遺伝子を標的としたショウジョウバエモデルの作成とその利用2019

    • Author(s)
      清水丈、笠井高士、吉田英樹、山口政光
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Remarks] 京都工芸繊維大学 応用生物学系 染色体工学教育研究分野 業績

    • URL

      http://www.bio.kit.ac.jp/laboratories/laboratories_11

    • Related Report
      2019 Annual Research Report

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Published: 2019-04-18   Modified: 2021-01-27  

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