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

在这个项目中，研究人员将应用非线性动力学和分叉理论的方法来更好地理解新月弯杆菌细胞分裂周期的时空动态的分子机制。控制细胞周期进程的生化网络由平行的和连续的、高度非线性的过程组成，包括正反馈和负反馈。这个网络中的许多蛋白质以细胞周期依赖的方式动态地定位在细胞的两极，为细胞周期调节提供了一个空间维度。在这个项目中，将通过数学建模和计算机仿真的方法，从动态系统的角度来探讨控制系统的复杂性。为此，研究人员将构建一个经过实验验证的动态数学模型，描述空间和时间上的相关分子事件。该模型将提供对当前细菌细胞周期控制的直观想法的严格描述，促进我们对细菌细胞分裂的理解，整合现有的实验数据，协调明显冲突的数据，识别数据差距，并提出新的实验设计。这项工作将数学建模、动力系统理论、分叉理论、渐近分析和数值计算的原理应用和发展。定量研究控制细胞分裂的分子机制将有助于我们理解细胞周期调控机制，也有助于理解发育生物学的一个基本问题(形态发生与细胞周期进程如何协调)。比较分析细菌和真核生物细胞周期的分子调控对进化生物学具有重要意义。最近的研究表明，在硫杆菌中发现的许多基因和机制在进化上与α-蛋白细菌的其他成员之间是保守的。因此，铜绿假单胞菌的细胞复制机制和研究人员将建立的数学模型可能会扩展到整个阿尔法蛋白细菌类别。几种α-蛋白细菌(包括中华根瘤菌、农杆菌、立克次体和布鲁氏菌)在广泛的环境、医疗和生物防务应用中具有重要作用。因此，对硫杆菌的生长、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间和空间控制的洞察可能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性理解和数学描述，并有助于扩大分子细胞生物学的量化转化。

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.