Integrated dynamics of temporal and spatial controls in the cell division cycle of Caulobacter crescentus

在本项目中，研究者将运用非线性动力学和分岔理论的方法来更好地理解调节新月形茎杆菌细胞分裂周期时空动力学的分子机制。在Caulobacter中，控制细胞周期进程的生化网络由平行和连续的高度非线性过程组成，包括正反馈和负反馈。该网络中的许多蛋白质以细胞周期依赖的方式动态定位在细胞的两极，为细胞周期调节提供了空间维度。在这个项目中，控制系统的复杂性将通过数学建模和计算机仿真从动态系统的角度来探讨。为此，研究人员将构建一个经过实验验证的动态数学模型，该模型将描述空间和时间中的相关分子事件。该模型将提供当前细菌细胞周期控制的直观想法的严格说明，推进我们对细菌细胞分裂的理解，整合现有的实验数据，调和明显冲突的数据，识别数据空白，并提出新的实验设计。数学建模，动力系统理论，分岔理论，渐近分析和数值计算的原理将被使用和推进这项工作。对茎状杆菌中控制细胞分裂的分子机制的定量研究将有助于我们对细胞周期调节机制的理解，也有助于我们理解发育生物学中的一个基本问题（形态发生如何与细胞周期进程协调）。对细菌和真核生物细胞周期的分子调控进行比较分析，对进化生物学具有深刻的见解。最近的研究表明，在Caulobacter中发现的许多基因和机制在α -变形杆菌的其他成员中是进化保守的。因此，茎状杆菌的细胞复制机制和研究人员将建立的数学模型可以扩展到整个α -变形杆菌类。几种α -变形菌（包括中华根瘤菌、农杆菌、立克次体和布鲁氏菌）在环境、医疗和生物战防御的广泛应用中发挥着重要作用。因此，这项对茎状杆菌生长、复制和分化的基础研究可能具有深远的意义。特别是，对基因表达和蛋白质相互作用的时空控制的深入了解可以为抗菌药物的合理设计提供新的线索。在更大的范围内，这项研究将有助于对生命系统动力学的概念理解和数学描述，并扩展分子细胞生物学的定量转化。

In this project, the investigators will apply the methods of nonlinear dynamics and bifurcation theory for developing a better understanding of the molecular mechanism regulating temporal and spatial dynamics of the cell division cycle in Caulobacter crescentus. The biochemical network controlling cell cycle progression in Caulobacter consists of parallel and consecutive, highly nonlinear processes, comprising positive and negative feedbacks. Many proteins of this network dynamically localize at the poles of the cell in a cell cycle-dependent manner, providing a spatial dimension to cell cycle regulation. In this project the complexity of the control system will be approached from a dynamical systems perspective, by means of mathematical modeling and computer simulation. To this end, the investigators will construct an experimentally verified, dynamical mathematical model that will describe the relevant molecular events in space and time. The model will provide a rigorous account of current intuitive ideas of bacterial cell cycle control, advance our understanding of bacterial cell division, integrate available experimental data, reconcile apparently conflicting data, identify data gaps, and suggest new experimental designs. Principles of mathematical modeling, dynamical systems theory, bifurcation theory, asymptotic analysis, and numerical computation will be used and advanced by this work.The quantitative study of the molecular mechanism controlling cell division in Caulobacter will contribute to our understanding of cell cycle regulatory mechanisms and also of a fundamental issue in developmental biology (how morphogenesis is coordinated with cell cycle progression). Comparative analysis of the molecular regulation of the cell cycle in bacteria and eukaryotes can be insightful for evolutionary biology. Recent studies have shown that many of genes and mechanisms discovered in Caulobacter are evolutionarily conserved among other members of the alpha-proteobacteria. Thus, the mechanism of cell replication in Caulobacter and the mathematical model that the investigators will develop may be extendable to the whole class of alpha-proteobacteria. Several alpha-proteobacteria (including Sinorhizobium, Agrobacterium, Rickettsia, and Brucella) have important roles in a wide range of environmental, medical and biowarfare-defense applications. Therefore, this fundamental research on Caulobacter growth, replication and differentiation may have far-reaching implications. In particular, insights gained into temporal and spatial control of gene expression and protein interactions could provide new clues for rational design of antibacterial agents. On a larger scale, this study will contribute to a conceptual understanding and mathematical description of the dynamics of living systems and to extending the quantitative transformation of molecular cell biology.