Combinatorial Exploration of Cellular Regulatory Network Design Principles

蜂窝调控网络设计原理的组合探索

• 批准号: 8056959
• 负责人: Russell Gordley
• 金额: $ 4.84万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056959
• 关键词: Architecture; Behavior; Biological; Biological Assay; Biological Process; Cells; Communication; Complex; Disease; Engineering; Environment; Family; Feedback; Genetic Recombination; Goals; Libraries; Malignant Neoplasms; Maps; Memory; Methods; Molecular; Molecular Bank; Output; Partner in relationship; Pathway interactions; Physiological; Proteins; Recurrence; Screening procedure; Sensory; Signaling Protein; Solutions; Stimulus; Structure; Systems Biology; Therapeutic; Yeasts; base; biological systems; combinatorial; complex biological systems; design; insight

DESCRIPTION (provided by applicant): Combinatorial Exploration of Cellular Regulatory Network Design Principles A major goal in systems biology is to understand how cells use molecular circuits to achieve complex physiological behaviors and how these behaviors break down in disease states like cancer. Although only a small fraction of existing networks have been well characterized, recurrent topologies have emerged for a variety of biological functions, suggesting that any particular behavior is encoded by a limited number of network structures. With the goal of rapidly identifying the structural 'solutions' for target behaviors, we propose to develop a synthetic biological (forward engineering) approach of screening combinatorial libraries of molecular circuits. My specific aims are to: 1) Develop methods to assemble combinatorial circuit libraries. As a testbed we will construct a library of synthetic positive feedback loops in the yeast mating pathway and screen these for memory behavior. 2) Develop a screen for a complex dynamic behavior-sensory adaptation. A recombination-based FACS assay will be developed to screen for cells that can transiently respond to a stimulus, but then automatically reset output despite sustained stimulus. Comparison of functional circuit architectures is expected to reveal global design principles-critical network topologies and parameters, and robust structural motifs-providing a quantitative blueprint for core circuit families capable of each target task. This analysis should provide fundamental insight into how complex circuits that achieve memory and adaptation can be built. In the long-term, the emerging map correlating network structure and function will guide the interpretation, therapeutic perturbation, and rational synthesis of biological systems. PUBLIC HEALTH RELEVANCE: Cells sense and respond to their environment using a molecular communication network composed of interacting proteins. Many diseases, including cancer, arise when alteration of a signaling protein changes the network's structure, resulting in a new cellular behavior. Our goal is to generate a map correlating network structure and function that will guide the understanding and therapeutic correction of complex biological systems.

描述(申请人提供)：细胞调控网络设计原则的组合探索系统生物学的一个主要目标是了解细胞如何使用分子电路来实现复杂的生理行为，以及这些行为如何在癌症等疾病状态下分解。尽管只有一小部分现有网络得到了很好的表征，但针对各种生物功能的重复拓扑已经出现，这表明任何特定的行为都是由有限数量的网络结构编码的。为了快速识别目标行为的结构“解决方案”，我们提出了一种筛选分子电路组合文库的合成生物学(正向工程)方法。我的具体目标是：1)开发组合电路库的组装方法。作为一个试验床，我们将在酵母交配途径中构建一个合成正反馈环库，并对这些环路进行记忆行为筛选。2)开发一种屏幕，用于复杂的动态行为-感觉适应。一种基于重组的流式细胞仪将被开发出来，以筛选能够对刺激做出瞬时反应，但随后在持续刺激下自动重置输出的细胞。功能电路体系结构的比较预计将揭示全球设计原则-关键网络拓扑和参数，以及健壮的结构主题-为能够完成每个目标任务的核心电路系列提供量化蓝图。这一分析应该为如何构建实现记忆和适应的复杂电路提供基本的洞察。从长远来看，将网络结构和功能联系起来的新地图将指导生物系统的解释、治疗扰动和合理合成。 与公共健康相关：细胞使用由相互作用的蛋白质组成的分子通信网络来感知和响应环境。当信号蛋白改变网络结构，导致新的细胞行为时，包括癌症在内的许多疾病就会发生。我们的目标是生成一张将网络结构和功能关联起来的地图，这将指导对复杂生物系统的理解和治疗纠正。