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）：基因调节网络属于生物功能的基础，并负责推动维持生命所需的各种细胞任务。对健康和患病状态中细胞功能进行全面描述将需要精确的定量了解基础相互作用的动力学。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，这些计算模型可用于了解模型生物中基因调节的复杂性。每个目标都将使用建模和实验的组合来研究特定的动态行为，以设计模拟自然系统，建立网络并确保其符合一般设计目标的合成网络，并通过实验测试其预测和假设来重新/NE计算模型。 /rst Aim将探测两个合成时钟网络的行为，以阐明其动态行为的关键属性。将开发新的微生物菌株，以探索和测试对网络组件的降解率变化​​和拷贝数变化的振荡响应的预测。第二个目的将调查生物时钟的使用来协调独立生物体的行为。建模将用于预测网络对各种驾驶和耦合机制的响应，并将合成时钟与天然途径耦合，以研究振荡性夹带和同步的可能性。第三目的建议构建可以处理和输出脉动信号的合成信号网络。将开发并重新/NED来描述单细胞级别基本信息处理的机制。在 /nal的目标中，将应用 /rst三个目标中合成微生物网络的经验用于在哺乳动物细胞中发展几个遗传回路。尽管应该保留许多基因表达的基本原理，但在哺乳动物细胞中发展相似功能的过程可能会深入了解特定细胞环境的方式A.Ect基因调节。每个网络将使用自定义的微0核设备在单细胞水平上使用0荧光显微镜进行监测。这些研究将为对生命传播至关重要的几种基本监管基序提供至关重要的见解。公共卫生的重新浮动：细胞的存活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，对不可预测的环境变化做出反应，并安装了针对压力的适当防御。许多疾病是由于单个基因或基因调节模块无法执行特定任务的结果，从而导致整体细胞活力的细分。该提案的核心目标是构建模仿天然网络功能的新型合成基因回路，以便对底层生物学功能的动态相互作用进行精确的定量理解。