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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(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有一个定量的了解，真核细胞周期是最基本和复杂的生物过程之一。这项建议的具体目标是通过数学建模和定量实验的紧密耦合，构建、分析和验证芽期酵母中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的数学模型。细胞周期检查点和开关在确保细胞周期机制的准确和可靠执行方面发挥着至关重要的作用。它们的缺陷，例如由于遗传扰动，可能会导致不适当的细胞增殖或染色体分离错误，这通常与肿瘤的发生有关。这项工作将有助于对酵母细胞周期调控的更深层次、定量和系统水平的了解，这些研究已经深刻地影响了我们对高等生物细胞周期控制和癌症机制的认识。本文将运用动力系统理论中的概念和方法来分析和理解这一复杂系统。将建立使用微流控装置的定量单细胞分析，为数学模型生成数据，并测试模型预测。具体目标是：(1)酵母细胞周期网络的全局计算分析-将对酵母细胞周期网络进行系统的计算分析，以研究系统的全局动态特性和结构稳定性，以确定系统对哪些扰动是健壮的，哪些是不健壮的。(2)将G1检查点作为固定点进行定量研究--将使用计算模型和定量实验相结合的方法来研究G1停滞的稳定性以及可能增加或降低这种稳定性的网络扰动。检查点是动力系统的固定点的假设将得到检验。(3)G1/S开关的定量研究--采用计算模型和定量实验相结合的方法，研究S相进入过程中的类开关行为。我们将研究电路拓扑在确保稳健的开关行为方面的作用。(4)主轴组件检查点和M/A开关的定量研究--将采用计算模型和定量实验相结合的方法来研究检查点止动和切换动力学的稳定性，重点研究多个反馈回路各自的作用和协同作用。