Analysis of abnormal splicing mechanism and application for thetreatment of Muscular Dystrophy

• Project/Area Number: 22603002
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: ケミカルバイオロジー
• Research Institution: Kyoto University (2011-2012); Tokyo Medical and Dental University (2010)
• Principal Investigator: KATAOKA Naoyuki 京都大学, 医学研究科, 准教授 (60346062)
• Co-Investigator(Renkei-kenkyūsha): HAGIWARA Masatoshi 京都大学, 医学研究科形態形成機構学, 講座 (10208423)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2010: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: スプライシング / ジストロフィン / 筋ジストロフィー / 低分子化合物 / レポーター

Research Abstract

We have tried to set up the treatment of Duchenne Muscular Dystrophy by promoting mutated exon skipping by using a chemical compound. We found that TG003, a specific inhibitor for Clk kinases, promotes exon skipping in the patient cells. We also comprehensively analyzed the effect of TG003 in pre-mRNA splicing and detected the introns whose excision is affected.

Research Products

• [Journal Article] hDbr1 is a nucleocytoplasmic shuttling protein with a protein phosphatase-like motif essential for debranching activity (2013)
  • Author(s): Kataoka, N. Hagiwara, M. and Ohno, M
  • Journal Title: Sci. Rep Volume: 3-1090 Issue: 1 Pages: 1090-1090
  • DOI: 10.1038/srep01090
  • NAID: 120005241441
  • Peer Reviewed / Open Access
• [Journal Article] Stress-responsive maturation of Clk1/4 pre-mRNAs promotes phosphorylation of SR splicing factor (2011)
  • Author(s): Ninomiya, K., Kataoka, N. and Hagiwara, M
  • Journal Title: Journal of Cell Biology Volume: 195 Pages: 27-40
• [Journal Article] Specific Y14 domains mediate its nucleo- cytoplasmic shuttling and association with spliced mRNA (2011)
  • Author(s): Kataoka, N., Diem, M. D., Yoshida, M., Hatai, C., Dobashi, I., Dreyfuss, G., Hagiwara, M. and Ohno, M
  • Journal Title: Sci. Rep Volume: 1 Issue: 1 Pages: 92-92
  • DOI: 10.1038/srep00092
  • Peer Reviewed
• [Journal Article] Chemical treatment enhances skipping of a mutated exon in the dystrophin gene (2011)
  • Author(s): Nishida A, Kataoka N, Takeshima Y,Yagi M, Awano, H, Ota, M, Itoh K, Hagiwara M, and Matsuo M
  • Journal Title: Nat Commun Volume: 2 Issue: 1 Pages: 308-308
  • DOI: 10.1038/ncomms1306
  • NAID: 120003001398
  • Peer Reviewed
• [Presentation] Modulators for splicing of IKBKAP gene, a responsible gene for Familial dysautonomia (2012)
  • Author(s): Kataoka, N., Yoshida, M., Usui, T., Sakuma, M. and Hagiwara, M
  • Organizer: Cold Spring Harbor Asia 2012 Conference on RNA Biology
  • Place of Presentation: Suzhou, China
• [Presentation] PUF60 is a Differentiation-Dependent Splicing Regulator Required for Myogenesis (2012)
  • Author(s): Kataoka N., Nojima,T., Oshiro-Ideue, T., Takeuchi, A., Kii, I. and Hagiwara, M
  • Organizer: The 22nd CDB meeting "RNA Sciences in Cell and Developmental Biology II"Riken CDB
  • Place of Presentation: Kobe Japan
• [Presentation] 家族性自律神経失調症原因遺伝子IKBKAPの異常スプライシング機構の解析 (2012)
  • Author(s): 片岡直行、吉田真弓、薄井知美、佐久間真紀、萩原正敏
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] PUF60は筋分化特異的な選択的スプライシングの調節因子であり、筋発生に必要である (2012)
  • Author(s): 片岡直行、野島孝之、大城-井手上杜子、武内章英、喜井勲、萩原正敏
  • Organizer: 第14回日本RNA学会年会
  • Place of Presentation: 仙台
• [Presentation] Clk特異的阻害剤TG003を用いたジストロフィン遺伝子におけるエクソンスキッピング促進機構の解析 (2012)
  • Author(s): 片岡直行、西田篤史、飯田慶、松尾雅文、萩原正敏
  • Organizer: 第7回日本ケミカルバイオロジー学会
  • Place of Presentation: 京都
• [Presentation] PUF60 is a Differentiation-Dependent Splicing Regulator Required for Myogenesis (2012)
  • Author(s): 片岡直行
  • Organizer: The 22nd CDB Meeting, RNA Sciences in Cell and Developmental Biology II
  • Place of Presentation: 神戸 理研CDB
• [Presentation] Search for modulators of tissue- or tumor-specific alternative splicing based on multi-color fluorescence minigene reporter (2011)
  • Author(s): 片岡直行
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜パシフィコ横浜
  • Year and Date: 2011-12-15
• [Presentation] Chemical treatment that enhances skipping of the mutated exon in the dystrophin gene (2011)
  • Author(s): 片岡直行
  • Organizer: The 16th Annual Meeting of the RNA Society
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2011-06-16
• [Presentation] Chemical treatment that enhances skipping of the mutated exon in the dystrophin gene (2011)
  • Author(s): 片岡直行
  • Organizer: 日本ケミカルバイオロジー学会第6回年会
  • Place of Presentation: 東京東京工業大学
  • Year and Date: 2011-05-25
• [Presentation] Chemical treatment of muscular dystrophy that enhances skipping of the mutated exon in the dystrophin gene (2011)
  • Author(s): Kataoka N., Nishida A., Takeshima Y., Yagi M., Awano H., Ota M., Itoh K.,Hagiwara M. and Matsuo M
  • Organizer: 17th Annual Meeting of the RNA Society
  • Place of Presentation: Kyoto, Japan
• [Presentation] Chemical treatment enhances skipping of a mutated exon in the dystrophin gene (2011)
  • Author(s): 片岡直行、西田篤史、竹島泰弘、八木麻理子、粟野宏之、大田光徳、伊東恭子、松尾雅文、萩原正敏
  • Organizer: 第6回日本ケミカルバイオロジー学会
  • Place of Presentation: 東京
• [Presentation] Chemical treatment of muscular dystrophy that enhances skipping of the mutated exon in the dystrophin gene (2010)
  • Author(s): Kataoka, N., et al.
  • Organizer: Cold Spring Harbor Asia Conferences "RNA Biology"
  • Place of Presentation: Suzhou, China
  • Year and Date: 2010-11-01
• [Presentation] 家族性自律神経失調症原因遺伝子IKBKAPの異常スプライシング機構の解析
  • Author(s): 片岡直行
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場
• [Presentation] Modulators for splicing of IKBKAP gene, a responsible gene for Familial dysautonomia
  • Author(s): 片岡直行
  • Organizer: Cold Spring Harbor Asia 2012 Conference on RNA Biology
  • Place of Presentation: Suzhou/China
• [Presentation] マルチカラー蛍光スプライシングレポーターを用いたPKM遺伝子選択的スプライシング機構の解析
  • Author(s): 片岡直行
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌芸文館
• [Presentation] PUF60は筋分化特異的な選択的スプライシングの調節因子であり、筋発生に必要である
  • Author(s): 片岡直行
  • Organizer: 第14回日本RNA学会年会
  • Place of Presentation: 仙台 東北大学百周年記念会館
• [Book] 細胞・特集「RNAバイオロジーの最先端」総論 RNAプロセシングに起因する疾患「RNA病」 (2012)
  • Author(s): 片岡直行
• [Book] 細胞・特集「RNAバイオロジーの最先端」mRNAを標的とした新しい疾患治療戦略 (2012)
  • Author(s): 片岡直行、萩原正敏
• [Book] 実験医学・増刊「疾患克服をめざしたケミカルバイオロジー」RNAを標的とした新しい創薬戦略 (2012)
  • Author(s): 片岡直行、萩原正敏
• [Book] 細胞工学・特集「RNAプロセシング異常」RNAスプライシング操作によるRNA病治療戦略 (2010)
  • Author(s): 片岡直行、萩原正敏
• [Remarks]
  • URL: http://www.dsk.med.kyoto-u.ac.jp/index.html
• [Remarks]
  • URL: http://www.anat1dadb.med.kyoto-u.ac.jp/Anat1DADB/HOME/HOME.html
• [Patent(Industrial Property Rights)] 遺伝性疾患の予防・改善剤 (2011)
  • Inventor(s): 萩原正敏、片岡直行、松尾雅文、西田篤史
  • Industrial Property Rights Holder: 国立大学法人神戸大学 国立大学法人東京医科歯科大学
  • Industrial Property Number: 2010-146699
  • Filing Date: 2011-06-27
• [Patent(Industrial Property Rights)] 遺伝性疾患の予防・改善剤 (2010)
  • Inventor(s): 萩原正敏、片岡直行、松尾雅文、西田篤史
  • Industrial Property Rights Holder: 国立大学法人東京医科歯科大学、国立大学法人神戸大学
  • Industrial Property Number: 2010-014669
  • Filing Date: 2010-06-28