Limits and Trade-offs of Feedback Control

反馈控制的限制和权衡

基本信息

批准号：
7597111
负责人：
Johan Paulsson
金额：
$ 33.88万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Negative feedback control is essential to make biological systems stable to internal and external perturbations. It is used to regulate everything from body temperature to gene expression, and its failure causes a range of human disorders. But our understanding of feedback in biology is incomplete and incoherent. Most systematic theoretical approaches are based on deterministic kinetics, poorly suited for microscopic cellular events, and few systems allow accurate experimental measurements of the numbers of individual molecules in a given cell. Prior work focused so closely on the details of each system that general guiding principles have been overlooked, in turn making detailed analysis difficult. We propose to address these problems by developing new mathematical approaches and systematically applying our novel experimental molecule counting assays to simple model systems. Our preliminary theory demonstrates hard limits on the ability of negative feedback to suppress fluctuations in cellular systems, and general frustration trade-offs where reducing one type of variation instead amplifies another. It also suggests creative mechanisms that minimize these problems, and remarkably enough, we have now found examples of these in biology. We propose to extend the individual theorems by integrating central concepts from statistical physics and control theory into a novel coherent framework that makes it possible to make exact quantitative statements about strongly nonlinear and exotic systems. The theory is also used to motivate, design and interpret quantitative experiments for two systems that promote virulence and drug resistance in Escherichia coli. We focus on replication control of bacterial plasmids, where noise suppression is essential. The unmatched tractability of plasmids allows us to systematically vary control loop properties and rigorously test the general theorems. We will compare these results with those for stress response sigma factor RpoS, where we believe negative feedback may instead enhance variation. PUBLIC HEALTH RELEVANCE: Our studies will help lay the groundwork for effective studies of randomness in biology: where it comes from, how it is controlled, what limits physics sets on how biological systems suppress noise, and the creative ways that biological systems exploit apparent loopholes in those limits. We believe this will expose new principles that will help us understand how biological systems evolved, and how they function in health and disease particularly in systems that promote drug resistance and virulence in bacteria.

描述（由申请人提供）：负反馈控制对于使生物系统具有稳定的内部和外部扰动至关重要。它用于调节从体温到基因表达的所有事物，其失败会导致一系列人类疾病。但是，我们对生物学反馈的理解是不完整和不一致的。大多数系统的理论方法是基于确定性动力学，适合微观细胞事件的不良动力学，很少有系统允许对给定细胞中个体分子的数量进行准确的实验测量。先前的工作非常关注每个系统的细节，以至于一般指导原则被忽略了，进而使详细的分析变得困难。我们建议通过开发新的数学方法来解决这些问题，并系统地将新型的实验分子计数测定法应用于简单的模型系统。我们的初步理论表明，负面反馈抑制细胞系统波动的能力以及一般的挫败感权衡的能力，而减少一种类型的变异可以放大另一种变化。它还提出了使这些问题最小化的创造性机制，而且非常值得注意的是，我们现在在生物学中找到了这些问题。我们建议通过将中心概念从统计物理和控制理论整合到一个新型的连贯框架中来扩展单个定理，从而使对强烈非线性和外来系统的精确定量陈述成为可能。该理论还用于激励，设计和解释两种促进大肠杆菌中毒力和耐药性的系统的定量实验。我们专注于对噪声抑制至关重要的细菌质粒的复制控制。质粒的无与伦比的障碍性使我们能够系统地改变控制环的性能并严格测试一般定理。我们将将这些结果与应力响应Sigma因子RPO进行比较，在这种情况下，我们认为负反馈可能会增强变化。公共卫生相关性：我们的研究将有助于为有效研究生物学的随机性研究奠定基础：它来自何处，如何控制，限制物理学对生物系统如何抑制噪声的限制以及生物系统在这些限制中利用明显的漏洞的创造性方式。我们认为，这将揭示新的原则，以帮助我们了解生物系统的发展方式，以及它们在健康和疾病中的作用，尤其是在促进细菌耐药性和毒力的系统中。