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Coordination mechanisms between cell division and chromosome segregation in E. coli

大肠杆菌细胞分裂和染色体分离之间的协调机制

基本信息

批准号：
10734826
负责人：
Jaan Mannik
金额：
$ 30.74万
依托单位：
UNIVERSITY OF TENNESSEE KNOXVILLE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734826
关键词：
Actins Anti-Bacterial Agents Antibiotics Bacteria Binding Biological Models Cell Cycle Cell Cycle Checkpoint Cell Survival Cell Wall Cell division Cell physiology Cells Chromosome Segregation Collaborations Complex Computer Models Coupling Cytosol DNA biosynthesis Data Escherichia coli Filament Genome Goals Growth Homologous Gene Individual Kinetics Knowledge Link Lipids Maps Membrane Methods Microfluidic Microchips Modeling Molecular Molecular Biology Molecular Genetics Molecular Structure Pathway interactions Peptidoglycan Pharmaceutical Preparations Physical condensation Play Positioning Attribute Process Proliferating Proteins Reaction Replication Initiation Research Role Structure Techniques Therapeutic Work constriction daughter cell design experimental study in vitro Assay in vivo knowledge integration macromolecular assembly model organism molecular dynamics novel recruit self assembly simulation superresolution microscopy targeted treatment three-dimensional modeling treadmill z-ring

项目摘要

PROJECT SUMMARY The goal of this proposal is to provide a mechanistic understanding of how cell division in bacteria is controlled at a molecular level. Understanding these mechanisms, which are broadly conserved among the bacteria, is important because it can reveal potential targets for new antibacterial agents that inhibit cell division and stop cell propagation. The division process in bacteria involves two stages. In the first distinct step, FtsZ protofilament assembly, the Z-ring, forms. In Escherichia coli, the model organism for this study, the first step occurs early in the cell cycle. Only after a significant delay, which can last half of the cell cycle, does the second stage of cell division start. In this later step, septal peptidoglycan synthesis begins, and the cell constricts. In this stage, more than two dozen proteins are involved, most of them in a complex referred to as the divisome. It is not yet understood what determines the onset of either the first or the second stage of the division, both of which are critical for the cell's survival. This significant gap in our knowledge exists even though many proteins involved in cell division are known and their pairwise binding interactions mapped out. The difficulty in understanding processes controlling cell division arises from the presence of a large number of different interactions within the divisome and of many pathways that are partially redundant. Moreover, the protein assemblies, which in most studies are viewed as static, are highly dynamic, turning over in a matter of seconds in an energy-dependent process such as treadmilling. The complexity of the problem requires not only further experiments but the integration of the existing experimental results into a comprehensive modeling framework. Accordingly, we combine state-of-the-art experimental methods with stochastic cell cycle simulations and 3D modeling of assembly reactions of proteins involved in cell division. On the latter front, we leverage our previous work and ongoing collaborations. In the experimental work, we use molecular biology and genetic methods alongside high throughput and super-resolution microscopy, and we develop novel microfluidic devices for this research. These techniques have already generated large amounts of information-rich data that, among other findings, have shed new light on processes leading to the assembly of Z-ring from individual FtsZ protofilaments and determining the role of DNA replication over the control of the progression of the second stage of the division. The proposed work aims to consolidate these past findings into a single mechanistic framework. The knowledge gained will enhance our understanding of fundamental cellular processes in bacteria and provide a basis for designing effective antibacterial therapies that target bacterial cell division.

项目概要该提案的目标是提供对如何控制细菌细胞分裂的机制理解在分子水平上。了解这些在细菌中广泛保守的机制非常重要重要的是因为它可以揭示抑制细胞分裂和停止的新型抗菌剂的潜在靶点细胞繁殖。细菌的分裂过程涉及两个阶段。在第一个独特的步骤中，FtsZ 原丝组件，Z 形环，形成。在本研究的模型生物大肠杆菌中，第一步发生在细胞周期。只有在持续半个细胞周期的显着延迟之后，细胞的第二阶段才会发生。分部开始。在后面的步骤中，隔膜肽聚糖开始合成，并且细胞收缩。在这个阶段，更多其中涉及超过两打蛋白质，其中大多数位于称为分裂体的复合物中。现在还没有了解什么决定了分裂的第一阶段或第二阶段的开始，这两个阶段都是对细胞的生存至关重要。尽管许多蛋白质涉及细胞分裂是已知的，并且它们的成对结合相互作用也已被绘制出来。理解上的困难控制细胞分裂的过程源于细胞内大量不同相互作用的存在分裂和许多部分冗余的途径。此外，蛋白质组装体，在大多数情况下研究被视为静态的，但实际上是高度动态的，在依赖能量的情况下在几秒钟内就会发生变化过程如跑步机。问题的复杂性不仅需要进一步的实验，而且需要将现有的实验结果整合到一个综合的建模框架中。据此，我们将最先进的实验方法与随机细胞周期模拟和 3D 建模相结合参与细胞分裂的蛋白质的组装反应。在后一方面，我们利用了之前的工作并持续的合作。在实验工作中，我们使用分子生物学和遗传学方法以及高吞吐量和超分辨率显微镜，我们为这项研究开发了新型微流体装置。这些技术已经生成了大量信息丰富的数据，除其他发现外，这些数据已经关于从单个 FtsZ 原丝组装 Z 形环的过程的新见解，并确定 DNA 复制在控制分裂第二阶段进程中的作用。拟议的工作的目的是将这些过去的发现整合到一个单一的机制框架中。所获得的知识将增强我们对细菌基本细胞过程的理解，并为设计提供基础针对细菌细胞分裂的有效抗菌疗法。