2021 Fiscal Year Final Research Report
Development of Artificial Transcription Factors for Cooperative Regulation of Cardiomyopathy-Related Mitochondrial and Nuclear Genes
| Project/Area Number |
19H03349
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
杉山 弘 京都大学, 理学研究科, 教授 (50183843)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | Transcription therapy / Epigenetic codes / Mitochondria / Reactive Oxygen Species / Energy metabolism / Nanoparticle / Immunotherapy / Heteroplasmy |
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| Outline of Final Research Achievements |
The overarching aim of this project to develop biomimetic epigenetic codes that could operate as smart transcription factors (SMART-TFs) and regulate nuclear and mitochondrial genes on demand was successfully achieved. We created a nuclear SMART-TF termed e-PIP-HoGu that recognizes specific DNA sequences with a flexible gap spacing and also decoded telomere dynamics. We demonstrated the bioefficacy of nuclear SMART-TFs to enhance cardiomyogenesis in stem cells, alter transcription in brain cancer stem cells and suppress tumor metastasis in a mouse model. Encouraged with these results, we explored and verified that a SMART-TF termed En-PGC-1 targeting the mitochondrial biogenesis could control AMPK pathway associated with cellular energy metabolism and synergize PD-1 blockade immunotherapy in a mouse model. We developed a mitochondrial SMART-TFs to achieve targeted elimination of mutated mitochondrial DNA in live cells and also demonstrated cellular reactive oxygen species production.
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| Free Research Field |
薬系化学および創薬科学関連
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| Academic Significance and Societal Importance of the Research Achievements |
現在、核とミトコンドリアが担うエネルギー代謝を特異的に調節する手法は存在していない。 SMART-TFでのAMPKの制御能を実証した本研究は、マスター調節因子が遺伝子転写を変更せずに正確にオンとオフを切り替える「転写療法」と呼ばれる新たな手法開発の可能性を示している。近年、伝染病・非伝染病への核酸ベースの治療法が多々報告されている。従来の治療法は、タンパク質間相互作用を対象とし、多くは患者間で異なる効果をもたらす。我々の核酸ベースの標的治療薬は、患者間で一貫した長期的な効果が期待されるという大きな利点がある。これらは情報学的手法を用いて、精密医療の分野での有用なツールとしての応用が期待される。
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