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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A model of the cell-autonomous mammalian circadian clock
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A model of the cell-autonomous mammalian circadian clock

机译：细胞自主哺乳动物生物钟的模型

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摘要

Circadian timekeeping by intracellular molecular clocks is evident widely in prokaryotes and eukaryotes. The clockworks are driven by autoregulatory feedback loops that lead to oscillating levels of components whose maxima are in fixed phase relationships with one another. These phase relationships are the key metric characterizing the operation of the clocks. In this study, we built a mathematical model from the regulatory structure of the intraceilular circadian clock in mice and identified its parameters using an iterative evolutionary strategy, with minimum cost achieved through conformance to phase separations seen in cell-autonomous oscillators. The model was evaluated against the experimentally observed cell-autonomous circadian phenotypes of gene knockouts, particularly retention of rhythmicity and changes in expression level of molecular clock components. These tests reveal excellent de novo predictive ability of the model. Furthermore, sensitivity analysis shows that these knockout phenotypes are robust to parameter perturbation.
机译：通过细胞内分子钟进行的昼夜节律在原核生物和真核生物中广泛存在。发条系统由自动调节反馈环路驱动，这些环路导致其最大值相互之间具有固定相位关系的组件发生振荡。这些相位关系是表征时钟工作的关键指标。在这项研究中，我们从小鼠小脑内生物钟的调控结构中建立了一个数学模型，并使用迭代进化策略确定了其参数，并通过符合细胞自主振荡器中的相分离来实现了最低成本。针对实验观察到的基因敲除的细胞自主性昼夜节律表型，特别是节律性的保留和分子钟成分表达水平的变化，对模型进行了评估。这些测试揭示了该模型出色的从头预测能力。此外，敏感性分析表明，这些敲除表型对参数摄动具有鲁棒性。

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  • 作者

    Henry P. Mirsky; Andrew C. Liu; David K. Welsh; Steve A. Kay; Francis J. Doyle lll;

  • 作者单位

    Program in Biomolecular Science and Engineering, University of California, Santa Barbara, CA 93106-9611;

    Department of Cell and Developmental Biology, Division of Biological Sciences Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121 Department of Biology, University of Memphis, Memphis, TN 38152;

    Department of Cell and Developmental Biology, Division of Biological Sciences Department of Psychiatry, University of California at San Diego, La Jolla, CA 92093 Veterans Affairs San Diego Healthcare System, San Diego, CA 92161;

    Department of Cell and Developmental Biology, Division of Biological Sciences;

    Program in Biomolecular Science and Engineering, University of California, Santa Barbara, CA 93106-9611 Department of Chemical Engineering, University of California, Santa Barbara, CA 93106-5080;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    cell-level model; evolutionary strategy; gene regulatory network; mathematical model; mouse;

    机译：单元级模型;进化策略;基因调控网络;数学模型;老鼠;

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