Development and Validation of Models for Gene Regulation

基因调控模型的开发和验证

• 批准号: 8053564
• 负责人: JEFF M HASTY
• 金额: $ 10万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053564
• 关键词: Accounting; Address; Adopted; Affect; Animal Model; Automobile Driving; Behavior; Biological Clocks; Biological Process; Biology; Biomedical Engineering; Cell Cycle; Cell Line; Cell Survival; Cell physiology; Cells; Clock protein; Cloning; Complex; Computational Biology; Computer Simulation; Coupled; Coupling; Data; Development; Devices; Disease; Dose; Eating; Engineered Gene; Engineering; Ensure; Environment; Escherichia coli; Feedback; Foundations; Frequencies; Gene Expression; Gene Expression Regulation; Genes; Genetic; Goals; Individual; Life; Mammalian Cell; Mammalian Genetics; Microfluidic Microchips; Microscopy; Modeling; Molecular; Molecular Biology; Monitor; Organism; Output; Pathway interactions; Phenotype; Physiologic pulse; Population; Procedures; Process; Production; Property; Public Health; Regulator Genes; Saccharomyces cerevisiae; Signal Transduction; Stress; Study models; Supervision; Synthetic Genes; System; Testing; Validation; Width; Work; analog; design; design and construction; environmental change; experience; information processing; insight; interdisciplinary approach; meetings; microbial; novel; protein degradation; research study; response; synthetic construct

DESCRIPTION (provided by applicant): Gene regulatory networks lay at the foundation of biological function and are responsible for driving the diverse cellular tasks required to sustain life. Developing a comprehensive description of cellular function in healthy and diseased states will require a precise quantitative understanding of the dynamics of the underlying interactions. This project will address this need by developing and experimentally validating computational models with predictive capabilities that can be used to understand the complexities of gene regulation in model organisms. Each aim will investigate a particular dynamic behavior, using a combination of modeling and experimentation to design a synthetic network that mimics a natural system, build the network and ensure that it meets the general design goals, and re/ne the computational model by experimentally testing its predictions and assumptions. The /rst aim will probe the behavior of two synthetic clock networks, in order to elucidate the key properties that de/ne their dynamic behavior. New microbial strains will be developed to explore and test predictions of the oscillatory response to changes in degradation rate and copy number of the network components. The second aim will investigate the use of biological clocks to coordinate behavior across a population of independent organisms. Modeling will be used to predict the network response to various driving and coupling mechanisms, and the synthetic clocks will be coupled to native pathways to investigate the possibilities of oscillatory entrainment and synchronization. The third aim proposes to construct synthetic signaling networks that can process and output pulsatile signals. A model will be developed and re/ned to describe the mechanisms of basic information processing at the single-cell level. In the /nal aim, experience with the synthetic microbial networks in the /rst three aims will be applied to develop several genetic circuits in mammalian cells. While many of the basic principles of gene expression should be conserved, the process of developing similar functionality in mammalian cells will likely yield insight into how the particular cellular environment a.ects gene regulation. Each network will be monitored with 0uorescence microscopy at the single-cell level using customized micro0uidic devices. These studies will provide crucial insight into several of the fundamental regulatory motifs that are essential for the propagation of life. PUBLIC HEALTH REVEVANCE: The survival of cells depends on their ability to carry out diverse cellular tasks such as driving the cell division cycle, responding to unpredictable environmental changes, and mounting an appropriate defense against stress. Many diseases arise as the result of individual genes or gene regulatory modules that fail to perform a speci/c task, leading to a breakdown of overall cellular viability. The central goal of this proposal is to construct, study, and model novel synthetic gene circuits that mimic the functionality of native networks, in order to develop a precise quantitative understanding of the dynamic interactions that underlay essential biological functions.

描述（由申请人提供）：基因调控网络是生物功能的基础，负责驱动维持生命所需的多种细胞任务。对健康和患病状态下的细胞功能进行全面的描述将需要对潜在相互作用的动态进行精确的定量理解。该项目将通过开发和实验验证具有预测能力的计算模型来满足这一需求，这些模型可用于了解模式生物中基因调控的复杂性。每个目标都将研究特定的动态行为，结合建模和实验来设计模仿自然系统的合成网络，构建网络并确保其满足总体设计目标，并通过实验测试重新/重新设计计算模型它的预测和假设。第一个目标将探测两个合成时钟网络的行为，以阐明定义其动态行为的关键属性。将开发新的微生物菌株来探索和测试对网络组件降解率和拷贝数变化的振荡响应的预测。第二个目标将研究如何使用生物钟来协调独立生物体群体的行为。建模将用于预测网络对各种驱动和耦合机制的响应，合成时钟将耦合到本地路径以研究振荡夹带和同步的可能性。第三个目标提出构建可以处理和输出脉动信号的合成信号网络。将开发和重新设计一个模型来描述单细胞水平的基本信息处理机制。在最终目标中，前三个目标中合成微生物网络的经验将应用于开发哺乳动物细胞中的多种遗传回路。虽然基因表达的许多基本原理应该被保留，但在哺乳动物细胞中开发类似功能的过程可能会深入了解特定的细胞环境如何影响基因调控。每个网络将使用定制的 micro0uidic 设备在单细胞水平上通过 0uorescent 显微镜进行监测。这些研究将为生命繁殖所必需的几个基本调控主题提供重要的见解。公共卫生启示：细胞的生存取决于它们执行各种细胞任务的能力，例如驱动细胞分裂周期、响应不可预测的环境变化以及针对压力建立适当的防御。许多疾病的出现是由于单个基因或基因调控模块无法执行特定任务，导致整体细胞活力崩溃。该提案的中心目标是构建、研究和建模模仿本地网络功能的新型合成基因电路，以便对构成基本生物功能的动态相互作用进行精确的定量理解。