• 研究課題をさがす
  • 研究者をさがす
  • KAKENの使い方
  1. 課題ページに戻る

2019 年度 実績報告書

心筋症関連ミトコンドリア・核内遺伝子の協奏的制御を可能にする人工転写因子の開発

研究課題

研究課題/領域番号 19H03349
研究機関京都大学

研究代表者

ナマシヴァヤム パンディアン  京都大学, 高等研究院, 講師 (20625446)

研究分担者 杉山 弘  京都大学, 理学研究科, 教授 (50183843)
研究期間 (年度) 2019-04-01 – 2022-03-31
キーワードピロールイミダゾールポリアミド / エピジェネティクス / 人工転写因子 / ナノテクノロジー / 心筋症
研究実績の概要

In this fiscal year, we have successfully performed proof-of-concept (POC) studies to use a multi-disciplinary approach essential in constructing nanoparticle-based epigenetic codes termed SMART-TFs for mitochondrial and nuclear genes. In particular, we explored a new direction of harnessing the nanopore sequencing for epitranscriptomics and artificial intelligence for bioimaging. We have successfully created a new version of synthetic biomimetic epigenetic code for nuclear genes termed e-PIP-HoGu capable of mimicking the natural transcription factors (TFs) in terms of structure and function. This novel small molecule not only have improved design to target specific DNA nucleic acid sequences with flexible gap spacings, but also are non-toxic, cell-permeable, water-soluble, and chemically stable. We have also screened and identified a biomimetic epigenetic code capable of triggering AMPK-related genes and ensue mitochondrial biogenesis in T-cells. A synthetic TF for the mesoderm determining stemness factor SOX2 was repurposed and we demonstrated its efficacy in a mouse model to trigger targeted suppression of metastasis. Also, an image-based artificial intelligence (AI) program was developed and we performed a POC to accurately predict tumor and COVID-19 progression. We also synthesized quantum-sized pre-version of SMART-TFs and demonstrated that it can specifically localize inside the mitochondria. We published five articles and have four more under review. The outreach activity this year also was well-received and facilitated new important collaborations.

現在までの達成度 (区分)
現在までの達成度 (区分)

2: おおむね順調に進展している

理由

We achieved our primary aim of successfully integrating diverse disciplines like nanotechnology, synthetic organic chemistry and molecular biology by introducing cutting-edge techniques like machine learning and nanopore sequencing. This fiscal year, we provided a strong platform with proof-of-concept studies upon which we can accelerate our future course of study to accomplish the milestones of our project to construct nanoparticle-based biomimetic epigenetic codes termed SMART-TFs for mitochondrial and nuclear genes. The successful creation of the dual-functional, epigenetically active small molecule capable of introducing targeted acetylation is an important leap for our project. We also were able to synthesize, characterize and sequentially assemble the functional and DNA-binding domains of the SMART-TFs. The incorporation of nanopore sequencing technology and artificial intelligence program further enhanced our research as we could now rapidly perform epigenome analysis. While the publication on the mitochondrial gene regulation and nanoparticle construction is still pending, our current results indicate that it is feasible to achieve SMART-TFs capable of switching ON and OFF our target gene(s) of interest. We also fostered our international collaboration with the JSPS exchange programs where Prof. Li Cai from Rutgers University, USA visited us for three months and our team member Takuya Hidaka visited AO Research Institute for two months. Taken together, we crossed the milestones mentioned in the project and may cover more new research areas this year.

今後の研究の推進方策

Encouraged with our proof-of-concept studies, we have been creating quantum-sized nanoparticles that are sequentially assembled with mitochondrial penetrating peptide and selective DNA-binding pyrrole-imidazole polyamides. We have screened and identified biomimetic epigenetic codes capable of inducing AMPK-related gene networks associated with mitochondrial biogenesis and alter the generation of reactive oxygen species. We are screening to identify functional molecules that can be incorporated into the SMART-TFs to precisely control ROS generation. Our chemical biology approach to enhance the detection efficiency of nanopore-sequencing technology is expected to not only contribute our research but also could establish a new methodology to identify the modification in nucleic acids. The artificial intelligence program reported in our POC study is expected to precisely detect the nuclear and mitochondrial localization efficacy of SMART-TFs. We are also exploring the materials capable of substituting the small molecules that can scavenge reactive oxygen species. We aim to make good use of our international collaborations and expect to summarize the research results and publish them in high impact research journals. Our future course of study will focus on evaluating the bioefficacy of our synthetic and SMART-TFs by employing them in a step-wise manner and analyze their effect on genetic and epigenetic profiles.

  • 研究成果

    (11件)

すべて 2020 2019 その他

すべて 雑誌論文 (5件) (うち国際共著 2件、 査読あり 5件) 学会発表 (3件) (うち招待講演 3件) 備考 (3件)

  • [雑誌論文] CGHF: A Computational Decision Support System for Glioma Classification Using Hybrid Radiomics and Stationary Wavelet-Based Features2020

    • 著者名/発表者名
      R. Kumar, A. Gupta, H.S. Arora, Ganesh N Pandian, B. Raman.
    • 雑誌名

      IEEE Access

      巻: ー ページ: ー

    • DOI

      10.1109/ACCESS.2020.2989193

    • 査読あり / 国際共著
  • [雑誌論文] Sequence-specific transcription control of mitochondrial DNA by MITO-PIP2020

    • 著者名/発表者名
      T. Hidaka, H. Sugiyama, Ganesh N. Pandian
    • 雑誌名

      Methods Mol. Biol.

      巻: ー ページ: ー

    • 査読あり
  • [雑誌論文] A synthetic transcription factor pair mimic for precise recruitment of an epigenetic modifier to the targeted DNA locus2020

    • 著者名/発表者名
      Yu Zutao、Ai Mengting、Samanta Soumen K.、Hashiya Fumitaka、Taniguchi Junichi、Asamitsu Sefan、Ikeda Shuji、Hashiya Kaori、Bando Toshikazu、Pandian Ganesh N.、Isaacs Lyle、Sugiyama Hiroshi
    • 雑誌名

      Chemical Communications

      巻: 56 ページ: 2296~2299

    • DOI

      10.1039/C9CC09608F

    • 査読あり / 国際共著
  • [雑誌論文] Targeted suppression of metastasis regulatory transcription factor SOX2 in various cancer cell lines using a sequence-specific designer pyrrole?imidazole polyamide2020

    • 著者名/発表者名
      Malinee Madhu、Kumar Alok、Hidaka Takuya、Horie Masanobu、Hasegawa Kouichi、Pandian Ganesh N.、Sugiyama Hiroshi
    • 雑誌名

      Bioorganic & Medicinal Chemistry

      巻: 28 ページ: 115248~115248

    • DOI

      10.1016/j.bmc.2019.115248

    • 査読あり
  • [雑誌論文] Therapeutic gene regulation using pyrrole?imidazole polyamides2019

    • 著者名/発表者名
      Yu Zutao、Pandian Ganesh N.、Hidaka Takuya、Sugiyama Hiroshi
    • 雑誌名

      Advanced Drug Delivery Reviews

      巻: 147 ページ: 66~85

    • DOI

      10.1016/j.addr.2019.02.001

    • 査読あり
  • [学会発表] Biomimetic nanomolecular codes2020

    • 著者名/発表者名
      Ganesh N. Pandian
    • 学会等名
      Shimane University Lecture Series
    • 招待講演
  • [学会発表] Biomimetic molecular codes for therapeutic gene control2019

    • 著者名/発表者名
      Ganesh N. Pandian
    • 学会等名
      Academia Sinica/iCeMS Joint symposium
    • 招待講演
  • [学会発表] DNA-based small molecule approach to control cancer-associated factors like RAS2019

    • 著者名/発表者名
      Ganesh N. Pandian
    • 学会等名
      First QNM-iCeMS symposium
    • 招待講演
  • [備考] Advancing gene therapies: PIP pip hurray!

    • URL

      https://www.icems.kyoto-u.ac.jp/en/news/5271

  • [備考] 進化する遺伝子治療:PIPで躍進

    • URL

      http://www.kyoto-u.ac.jp/ja/research/research_results/2019/200115_1.html

  • [備考] Advancing gene therapies: PIP pip hurray!

    • URL

      https://www.asiaresearchnews.com/content/advancing-gene-therapies-pip-pip-hurray?fbclid=IwAR2z-kP2XPAeriLIeVUtptA8QKl0Pd7KAtCi2wHxN9W0boT36QDqpzSAeek

URL: 

公開日: 2021-01-27  

サービス概要 検索マニュアル よくある質問 お知らせ 利用規程 科研費による研究の帰属

Powered by NII kakenhi