Nonequilibrium Dynamics and Thermodynamics of the Cell Cycle

石溪大学的王进在化学系生命过程化学项目的支持下，以发芽酵母为模型系统，开发了探索真核生物细胞周期的综合理论和计算方法。物理学部的生命系统物理学项目、分子和细胞生物科学部的细胞动力学和功能集群以及分子和细胞生物科学部的系统和合成生物学集群也为这一奖项做出了贡献。细胞周期对细胞的复制和分裂至关重要。它控制着细胞的增殖和发育-生命的基础。这个项目正在利用一种独特的方法组合来了解细胞周期的起源和驱动力。通过计算分析，确定了细胞周期过程中的关键基因和调节因子，这些基因和调控因子对于保证细胞的正常功能至关重要，以便与实验数据进行比较。王教授的工作可能会导致对细胞生物学功能的新理解，这对维持正常的细胞功能具有重要意义，而正常细胞功能对人类健康和疾病预防至关重要。在项目研究的基础上，一个新的教学模块被整合到系级系统生物学课程中。这项研究的跨学科性质是为来自不同背景的学生提供在相互学习、合作的环境中培训他们的机会，使他们准备好解决这些领域的结合点的问题。细胞周期的研究对于理解单个细胞的生命是必不可少的，单个细胞是生命系统的基本单位。王教授和他的团队正在开发的全球动力学理论将细胞潜在的基因调控网络模拟为一个化学反应网络，基因表达水平扮演着化学态浓度的角色。基因表达状态之间转换的驱动力来源于由稳态概率确定的非平衡有效势和系统状态之间的旋转稳态通量。稳态概率通量量化了非平衡和不可逆行为的程度，为从动力学的角度描述系统的热力学提供了桥梁。该项目正在研究根据基因调控网络开发细胞周期的动态系统模型。研究人员还在开发一种从能量输入、能量成本和熵产生的角度来描述细胞周期的非平衡热力学理论。该团队还将动力系统和非平衡动力学模型结合起来，以实现对细胞周期速度、一致性等生物可观察性的预测，并利用敏感性分析来确定关键基因和调节因子。模型预测与实验合作者肖杰的基因表达动力学和相关性的体内荧光测量结果进行了比较。非平衡动力学和热力学理论是普遍的，可以应用于不同生物体的细胞周期过程和相关的潜在调控网络。该项目使人们能够更深入地、定量地了解细胞周期，并将其应用于正常功能维护和疾病预防。教育活动包括组织研讨会，为期一个月的访问学者计划，以及关于项目跨学科主题的研讨会。学生接受来自化学、动力系统理论和物理学的理论和建模技术的培训，以及细胞生物学的应用。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Jin Wang of Stony Brook University is supported by the Chemistry of Life Processes Program in the Division of Chemistry to develop integrated theoretical and computational methods for exploring the cell cycle of eukaryotic organisms, using budding yeast as a model system. The Physics of Living Systems Program in the Division of Physics, the Cellular Dynamics and Function Cluster in the Division of Molecular and Cellular Biosciences, and the Systems and Synthetic Biology Cluster in the Division of Molecular and Cellular Biosciences also contribute to this award. The cell cycle is critical to the replication and division of a cell. It governs cellular proliferation and development---the basis of life. This project is utilizing a unique combination of approaches to understand the origin and driving forces of the cell cycle. Key genes and regulators of the cell cycle process, critical to guaranteeing normal cellular function, are identified through computational analysis, for comparison with experimental data. Professor Wang's work may lead to a new understanding of the biological functions of the cell, with implications for the maintenance of normal cell function, critical to human health and prevention of disease. A new teaching module, based on research from the project, is integrated into the departmental systems biology course. The interdisciplinary nature of the research is providing opportunities for training students from different backgrounds in a mutual learning, collaborative environment, preparing them to tackle problems at the nexus of these fields.The study of the cell cycle is essential to understanding the life of a single cell, the basic unit of living systems. The global dynamical theory that Professor Wang and his group are developing models the underlying gene regulatory network of the cell as a chemical reaction network, with gene expression levels playing the role of chemical state concentrations. The driving forces for transitions between gene expression states originate in a combination of a nonequilibrium effective potential determined by the steady state probability and the rotational steady state flux between states of the system. The steady state probability flux quantifies the extent of nonequilibriumness and irreversible behavior, and provides the bridge for describing the thermodynamics of the system in terms of its dynamics. The project is investigating the development of a dynamical systems model of the cell cycle in terms of the gene regulatory network. Researchers are also developing a nonequilibrium thermodynamic theory of the cell cycle in terms of energy input, energy cost, and entropy production. The team also couples the dynamical systems and nonequilibrium dynamics models to enable predictions of biological observables such as cell cycle speed, coherence, with utilization of sensitivity analysis to identify key genes and regulators. Model predictions are being compared against time-dependent in vivo fluorescence measurements of gene expression dynamics and correlations from experimental collaborator Jie Xiao. The nonequilibrium dynamics and thermodynamic theory is general and can be applied to cell cycle processes in different organisms and associated underlying regulatory networks. This project is enabling a deeper, quantitative understanding of the cell cycle, with applications to normal function maintenance and disease prevention. Educational activities include organization of a workshop, month-long program of visiting scholars, and seminars on the interdisciplinary topics of the project. Students are trained in theory and modeling techniques from chemistry, dynamical systems theory, and physics, with applications to cell biology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.