| Project/Area Number |
23K27298
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| Project/Area Number (Other) |
23H02607 (2023)
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Multi-year Fund (2024)
Single-year Grants (2023) |
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| Section | 一般 |
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| Review Section |
Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
Basic Section 47050:Environmental and natural pharmaceutical resources-related
Sections That Are Subject to Joint Review: Basic Section47010:Pharmaceutical chemistry and drug development sciences-related , Basic Section47050:Environmental and natural pharmaceutical resources-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, 高等研究院, 研究員 (50183843)
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| Project Period (FY) |
2024-04-01 – 2026-03-31
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| Project Status |
Granted (Fiscal Year 2024)
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| Budget Amount *help |
¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
Fiscal Year 2025: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2024: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2023: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
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| Keywords | ミトコンドリア / 転写療法 / 活性酸素種 / 皮膚細胞の若返り / エピジェネティックコード |
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| Outline of Research at the Start |
細胞レベルでは加齢による皮膚の老化に伴って、ミトコンドリアのレドックス恒常性が低下し、遺伝子転写機構の変化・エピゲノムの乱れ・活性酸素種 (ROS) の過剰な産生が行われる。既存の生物活性化合物により、核やミトコンドリアによるROSを調節する複雑な遺伝子転写機構の分子成分を個別に標的とすることは可能である。しかし、複数の標的をオンデマンドで協調的に調節するプログラム可能な合成ツールは存在していない。本研究では、皮膚細胞の若返りに関与する複雑な核およびミトコンドリア遺伝子転写機構の協調的な調節を可能にするナノ粒子ベースの人工転写因子 (PRO-TF) を構築し、評価することを目標とする。
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| Outline of Annual Research Achievements |
This fiscal year we have pioneered transcription theranostic platforms to achieve cellular rejuvenation by targeting inflammaging at the interface of epigenetic regulation, mitochondrial health, and nanotechnology. Biomass-derived and nitrogen-doped carbon quantum dots were developed as non-toxic, stimuli-responsive biosensors capable of detecting and modulating inflammatory signals, such as IL-6 and ROS, in vitro and in vivo. A synthetic epigenetic-metabolic modulator enhanced PGC1α-driven mitochondrial biogenesis,restored mitochondrial function, reduced oxidative stress, and improved metabolic flexibility in insulin-resistant cells. Complementary tools like AI-designed small molecules and DNA-based nanostructures enabled useful tools to achieve targeted transcription therapeutics.
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
The project advanced more swiftly than planned, with key milestones completed ahead of schedule. Foundational experimental systems were established, expediting the design and validation of transcription-based theranostic platforms for cellular rejuvenation. Interdisciplinary collaborations enabled the seamless convergence of nanoparticle engineering, targeted bioimaging, and epigenetic-mitochondrial modulation, resulting in eight peer-reviewed publications. Through the institutional exchange framework, Skintegrity faculty members and early-career researchers engaged in bilateral visits between Kyoto University and the University of Zurich, enhancing collaborative synergies. Also, Kyoto University launched the INtelligent ChemBioInformatics, a multi-lateral initiative on healthy aging.
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| Strategy for Future Research Activity |
Building on our successful development of carbon-based biosensors and mitochondrial immunomodulators, this year’s research will focus on fine-tuning the transcription therapy tools for rejuvenation of aged skin cells. Using artificially-induced senescent cells and aged fibroblast models, we will assess transcriptional responses and mtDNA heteroplasmy via qPCR and transcriptome profiling. Dual treatment will clarify cross-talk between nuclear and mitochondrial targets and their influence on ROS regulation via DCFH-DA flow cytometry, collagen profiling, marker identification using FACS. Telomere-targeting PIPs will be used to track rejuvenation potential, while a microfluidic skin-on-chip model enable 3D model to fast-track the translation of our targeted transcription therapeutics.
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