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Study of mitochondria-associated diseases by pathogenic mitochondrial DNA replication delay

Research Project

Project/Area Number 25461573
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pediatrics
Research InstitutionChiba Cancer Center (Research Institute)

Principal Investigator

Koshikawa Nobuko  千葉県がんセンター(研究所), がん遺伝創薬研究室, 主席研究員 (90260249)

Co-Investigator(Kenkyū-buntansha) WATANABE Takayoshi  千葉県がんセンター研究所, がん遺伝創薬研究室, 研究員 (60526060)
NAGASE Hiroki  千葉県がんセンター研究所, がん遺伝創薬研究室, 研究所長 (90322073)
Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords病因性ミトコンドリアDNA / ミトコンドリア病 / PIポリアミド / ミットコンドリア病 / MELAS / ミトコンドリアDNA / mtDNA異常 / cybrid / PIポリアミドFITC修飾 / PI ポリアミド / mtDNA 変異 / 疾患特異的mtDNA変異
Outline of Final Research Achievements

Mitochondrial DNA (mtDNA) mutation 3243 A>G is one of the causes of MELAS. We designed Pyrrole/Imidazole polyamide (PIP) in order to inhibit this gene expression (PIP2). HeLamt3243 cybrids have 3243A>G mutation, at different rates. A cybrid was treated with FITC labeled PIP2. Mitochondria were stained by FITC and were visible as dots, so were mtDNAs also stained. But FITC (equal PIP2) was eliminated from mitochondria 48 hours after treatment. In order to extend the residence time of PIP in mitochondria, triphenylphosphonium (TPP) was conjugated with fluorochrome and was introduced to the cybrid with 3243A>G mutation. Mitochondria were stained by TPP conjugated fluorochrome and kept it’s fluorescence for at least 48 hours on mitochondria. It is suggested that TPP conjugated compound reached mitochondria and remained bound for at least 48 hours post treatment. Then PIP conjugated TPP was synthesized (PIP-TPP). A cybrid with 3243 A>G mutation is being treated with PIP-TPP.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • 2013 Research-status Report
  • Research Products

    (3 results)

All 2015 2014

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (2 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole-imidazole polyamide conjugate.2014

    • Author(s)
      Hiraoka K, Inoue T, Taylor RD, Watanabe T, Koshikawa N, Yoda H, Shinohara K, Takatori A, Sugimoto H, Maru Y, Denda T, Fujiwara K, Balmain A, Ozaki T, Bando T, Sugiyama H, Nagase H.
    • Journal Title

      Nat. Commun.

      Volume: 6 Issue: 1 Pages: 6706-6706

    • DOI

      10.1038/ncomms7706

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] A novel alkylating pyrrole-imidazole polyamide, KR12, specifically recognized mutant KRAS genes and potently induces cell death2015

    • Author(s)
      K Hiraoka, T Inoue, H Yoda, A Takatori, T Watanabe, N Koshikawa, T Ozaki, H Nagase
    • Organizer
      America Association for Cancer Research Annual Meeting 2015
    • Place of Presentation
      アメリカ合衆国
    • Year and Date
      2015-04-22
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] KRAS mutation specific alkylating pyrrole-imidazole polyamide (KR12) suppresses mutant KRAS expression and inhibits tumor growth by showing accumulation in KRAS mutant xenografts2015

    • Author(s)
      T Inoue,K Hiraoka, Y Suzuki, H Yoda, A Takatori, N Koshikawa, T Ozaki, H Nagase
    • Organizer
      America Association for Cancer Research Annual Meeting 2015
    • Place of Presentation
      アメリカ合衆国
    • Year and Date
      2015-04-22
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research

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Published: 2014-07-25   Modified: 2019-07-29  

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