Quantitative studies of cell cycle checkpoints and switches

细胞周期检查点和开关的定量研究

基本信息

批准号：
8678947
负责人：
DAVID Owen MORGAN
金额：
$ 38.01万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-08 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8678947
关键词：
Address Anaphase Attention Back Behavior Biochemical Biological Assay Biological Process Cell Cycle Cell Cycle Checkpoint Cell Cycle Regulation Cell Proliferation Cell division Cells Chromosome Segregation Complex Computer Simulation Coupled Coupling Data Defect Ensure Eukaryotic Cell Event Feedback G1 Arrest Gene Mutation Genetic Genomic Instability Goals Investigation Knowledge Lead Malignant Neoplasms Measures Metaphase Methods Microfluidic Microchips Modeling Modeling of Cellular Pathways Monitor Noise Organism Phosphorylation Play Process Property Regulation Research Role S Phase Saccharomyces cerevisiae Saccharomycetales Signal Transduction Stress System Systems Theory Testing Time Time Study Work Yeasts biological systems feeding in vivo insight mathematical model mutant network architecture novel therapeutics research study residence signal processing tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this research is to gain a quantitative understanding of the regulation of the eukaryotic cell cycle, one of the most fundamental and complex biological processes. The specific goal of this proposal is to construct, analyze and validate mathematical models for several key cell cycle checkpoints and switches as well as for the entire cell cycle network in the budding yeast Saccharomyces cerevisiae, through a close coupling between mathematical modeling and quantitative experimentation. Cell cycle checkpoints and switches play essential roles in ensuring precise and robust execution of the cell cycle machinery. Defects in them, e.g. due to genetic perturbations, can lead to inappropriate cell proliferation or errors in chromosome segregation, which are commonly associated with tumorigenesis. This work will contribute to a deeper, quantitative and systems level understanding of the yeast cell cycle regulation, the studies of which have profoundly impacted on our knowledge about cell cycle control in higher organisms and on the mechanisms of cancer. Concepts and methods from dynamical systems theory will be applied here to analyze and comprehend this complex system. Quantitative single-cell assays using microfluidic devices will be set up to generate data for the mathematical model and to test the model predictions. The specific aims are: (1) Global computational analyses of the yeast cell cycle network - Systematic computational analyses on the yeast cell cycle network will be carried out to investigate the global dynamic properties and the structural stability of the system to identify what kinds of perturbations the system is robust to and what is not. (2) Quantitative study of the G1 checkpoint as a fixed point - Computational models and quantitative experiments will be used together to investigate the stability of the G1 arrest and the network perturbations that can increase or decrease this stability. The hypothesis that the checkpoint is a dynamical system's fixed point will be tested. (3) Quantitative study of the G1/S switch - Computational models and quantitative experiments will be used together to investigate the switch-like behavior in S-phase entry. The role of the circuit topology in ensuring a robust switching behavior will be studied. (4) Quantitative study of the spindle assembly checkpoint and the M/A switch - Computational modeling and quantitative experiments will be used together to investigate the stability of the checkpoint arrest and the switching dynamics, focusing on the respective and synergistic roles of the multiple feedback loops.

描述（由申请人提供）：这项研究的长期目标是对真核细胞周期的调节进行定量理解，这是最基本，最复杂的生物学过程之一。该提案的具体目标是通过数学建模和定量实验之间的紧密耦合，为几个关键的细胞周期检查点和开关以及整个细胞周期网络构建，分析和验证数学模型以及整个细胞周期网络。细胞周期检查点和开关在确保细胞周期机械的精确执行中起着至关重要的作用。其中的缺陷，例如由于遗传扰动，可能导致不适当的细胞增殖或染色体分离中的误差，这通常与肿瘤发生有关。这项工作将有助于对酵母细胞周期调节的更深入，定量和系统水平的理解，这些研究对我们对高等生物体和癌症机制的细胞周期控制的了解深远影响。动态系统理论的概念和方法将在此处应用于分析和理解这一复杂系统。使用微流体设备的定量单细胞测定将设置以生成数学模型的数据并测试模型预测。具体目的是：（1）将对酵母细胞周期网络的全局计算分析 - 将在酵母细胞周期网络上进行系统的计算分析，以研究全局动态属性和系统的结构稳定性，以确定系统的哪种扰动，并且不是什么。（2）将G1检查点作为固定点的定量研究 - 计算模型和定量实验将共同研究G1停滞的稳定性以及可以提高或降低此稳定性的网络扰动。将测试检查点是动态系统的固定点的假设。（3）G1/S开关的定量研究 - 计算模型和定量实验将共同研究S阶段进入中类似开关的行为。将研究电路拓扑在确保强大的切换行为方面的作用。（4）主轴组件检查点和M/A开关 - 计算建模和定量实验的定量研究将共同研究检查点停滞和开关动力学的稳定性，重点是多个反馈LOOP的相应和协同作用。