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    Home > Biochemistry News > Biotechnology News > Liu Tao's team published an insulin-secreting cell therapy system regulated by unnatural amino acids in "Nature Chemical Biology"

    Liu Tao's team published an insulin-secreting cell therapy system regulated by unnatural amino acids in "Nature Chemical Biology"

    • Last Update: 2022-01-23
    • Source: Internet
    • Author: User
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    2021 Nian 11 Yue 15 days, my room Tao researcher team in the field of chemical biology leading journals Nature Chemical Biology ( IF = 15.
    0
    ), published online the latest research results  "Genetic code Expanded the Cell-based Therapy for treating Diabetes in the MICE"
    .

    In recent years, with the successful launch of CAR-T cells, cell therapy designed using synthetic biology has shown broad prospects for disease treatment
    .
    The basic principle is to assemble a drug target regulatory switch in cells, and under the action of exogenous stimulation signals, cells regulate the synthesis of target proteins

    .
    When the cell therapy system is applied to diabetes, the expression of insulin can be regulated by oral small molecules as exogenous stimulation signals, avoiding the pain caused by insulin injection

    .
    However, current cell therapy strategies are difficult to achieve rapid signaling regulation, which limits their application in diseases that require timely intervention, such as diabetes

    .
    Among them, the main reason is the lack of synthetic biology tools for rapid regulation

    .
    Current regulatory tools mainly focus on transcription factor-mediated regulation at the transcriptional level.
    The regulatory process is complex and the protein expression time is slow

    .

    In response to this problem, Liu Tao's team has developed a non-natural amino acid-regulated insulin cell therapy system ( Noncanonical Amino acids (ncAAs)-triggered Therapeutic Switch, NATS ) using gene codon expansion technology , which bypasses transcriptional regulation and directly regulates proteins at the translational level.
    expression
    (pictured)
    .
    This research complements the protein regulatory switch tool library in synthetic biology, and also provides new ideas for the application and innovation of gene codon expansion technology
    .

     

     

    The NAST system rapidly regulates protein expression at the translational level

     

    Gene codon expansion technology uses aminoacyl- tRNA synthetase and tRNA molecule pair that can recognize ncAA , reads through the ectopic amber codon of mRNA , and inserts ncAA into protein.
    This technology has become an important protein site-directed modification technology
    .
    Liu Tao's team integrated the protein translation mechanism of ncAA aminoacyl tRNA into the mammalian cell genome, and constructed an engineered cell line that can reversibly regulate insulin expression at the translational level .
    Using cell embedding technology, the researchers encapsulated NATS cells with a selectively permeable membrane and then transplanted them into mice, so that the transplanted cells could obtain nutrient molecules and avoid the attack of mouse immune cells .
    By oral administration of ncAA , mice can obtain ncAA dose-dependent target protein expression .
    After a single oral administration of ncAA in diabetic mice , blood glucose can be significantly reduced within 90 minutes .
    Diabetes is a chronic disease requiring lifelong medication .






    To prove the long-term therapeutic effect of the NATS system, the researchers conducted a one-month drug efficacy and toxicity experiment
    .
    The results showed that diabetic mice transplanted with
    NATS cells could achieve sustained insulin expression and glycemic control, and no abnormalities in body weight and physiological and biochemical indicators were observed
    .
    This study applies gene codon expansion technology to the field of cell therapy, which makes up for the insufficiency of traditional transcriptional regulation tools and provides new ideas for cell therapy strategies for diabetes
    .

     

     

    From left: Huang Yujia, researcher Liu Tao, Chen Chao, researcher Ye Haifeng

     

    Chen Chao and Huang Yujia, Ph.
    D.
    students from Peking University, and Yu Guiling, Ph.
    D.
    student from East China Normal University are the co-first authors of the paper.
    Researcher Liu Tao and Professor Ye Haifeng from the School of Life Sciences of East China Normal University are the co-corresponding authors

    .
    The pharmacokinetic experiments of this study were assisted by Sun Yi, a professor at the School of Pharmacy, Peking University

    .
    The research has won the Beijing Outstanding Youth Fund, the National Natural Science Outstanding Youth Fund, the National "Major New Drug Creation" project, the Ministry of Science and Technology's key project of synthetic biology, the Shanghai Science and Technology Commission's major synthetic biology project, and the Shenzhen Institute of Synthetic Biology Innovation.
    Support for projects such as open funds

    .

    Paper link: https://  

    Introduction to Researcher Liu Tao

     

     

    Liu Tao is a researcher of the School of Pharmacy, Peking University, a doctoral supervisor, the director of the Department of Molecular and Cellular Pharmacology, the PI of the State Key Laboratory of Natural Medicines and Biomimetic Drugs, and the PI of the Interdisciplinary Center of Chemical Biology, Peking University .
    He has been funded by Peking University Hundred Talents, High-level Introduction of Young Talents by the Organization Department of the CPC Central Committee, National Excellent Youth, Beijing Outstanding Youth and other projects .
    He is a member of the Synthetic Biology Branch of the China Medical Biotechnology Association, a member of the Youth Working Committee of the China Biomedical Engineering Society, and won the Chinese Pharmaceutical Association - Yiling Biomedical Youth Award, Peking University Bayer Researcher Award and Wang Xuan Young Scholar Award .
    As the corresponding author, he has published nearly 20 scientific papers in Nature Chem Biol, Mol CellSci Adv ,  JACSAngew.
    Chem.
    Int.
    Ed.
    and other journals .
    He serves as the young editorial board member of Chin Chem Lett , the editorial board member of Frontiers in Chemistry , the guest editorial board member of Journal of Molecular Biology , etc.
    The research focuses on protein site-specific modification technology, and has developed innovative protein drugs containing artificial amino acids, which are used in various fields such as tumor and gene therapy, thus promoting the upgrading of biological drugs .



     


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