Integration of Diverse Inputs Determines Developmental Outcomes

不同输入的整合决定发展结果

• 批准号: 9243266
• 负责人: Gabor Balazsi
• 金额: $ 40.55万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243266
• 关键词: Anti-Bacterial Agents; Bacteria; Bacterial Genome; Bacterial Infections; Bacteriophage lambda; Bacteriophages; Biological Models; Cell Death; Cell Signaling Process; Cell Size; Cell physiology; Cells; Color; Computer Simulation; Cytolysis; DNA; Data; Decision Making; Dependence; Development; Developmental Process; Disease; Ensure; Environment; Environmental Risk Factor; Escherichia coli; Escherichia coli Infections; Event; Frequencies; Gene Dosage; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genome; Goals; Growth; HIV; Health; Human; Individual; Individuality; Infection; Injection of therapeutic agent; Investigation; Label; Lysogeny; Lytic; Maintenance; Measures; Messenger RNA; Methods; Modeling; Molecular; Monitor; Movement; Nature; Noise; Nutrient; Organism; Outcome; Pathway interactions; Population; Process; Production; Regulator Genes; Reporter; Resolution; Signal Transduction; Stem cells; Study models; System; Variant; Viral; Virus; Virus Replication; Voting; Work; developmental genetics; experimental study; high resolution imaging; improved; innovation; insight; integration site; live cell microscopy; mathematical model; mutant; neglect; new technology; novel; novel therapeutics; public health relevance; response; simulation; single molecule; spatiotemporal

 DESCRIPTION (provided by applicant): The focus of this project is to elucidate the underlying mechanism for lysis/lysogeny decision making in E. coli upon infection by phage lambda, a paradigmatic system for cell-fate determination and developmental genetic networks. This system offers appealing opportunities to examine how the stochasticity of gene expression from a single gene and spatial aspects involved in the process contribute to the stochasticity-determinism duality nature of the decision-making process which involves a regulatory genetic network. Through our recent study using live-cell microscopy, we hypothesized a different and surprising decision-making scenario from the classical picture. However, the underlying mechanism remains unclear. We propose a systematic investigation of this system in much more detail at the single-cell/single-virus/single-molecule level. The proposal has three specific aims. The first Aim focuses on elucidating how individual phage genome contributes to the lysis/lysogeny decision. It includes exploring how the spatiotemporal information of phage DNA inside the cell correlates with cell fates, how the description of lysis/lysogeny decision in response to the known deterministic factors (e.g. number of infecting phages per cell and cell size) is improved when examined at the single phage-DNA level, and how phages cooperate or compete with each other through mixed infection experiments. The second Aim focuses on determining the sensitivity and responsiveness of the lysis/lysogeny over a full spectrum of distinct growth conditions and phage factors systematically and investigating the gene expression with high-resolution and high-throughput methods. The final Aim is to develop mathematical and computational models of gene expression that account for phage replication, to explain the influence of various genetic and environmental factors on the lysis/lysogeny decision. Overall, our hope is to reach a quantitative understanding of how various deterministic factors and stochasticity contribute to the outcome of a well-known, but incompletely understood developmental process.

 描述（由申请人提供）：本项目的重点是阐明大肠杆菌中溶解/溶原性决策的潜在机制。大肠杆菌感染的噬菌体λ，细胞命运决定和发育遗传网络的典范系统。该系统提供了有吸引力的机会，研究如何从一个单一的基因和空间方面参与的过程中的基因表达的随机性，有助于随机决定论的二重性的决策过程，其中涉及到一个监管的遗传网络。通过我们最近使用活细胞显微镜的研究，我们假设了一个与经典图片不同的令人惊讶的决策场景。然而，其潜在机制仍不清楚。我们建议在单细胞/单病毒/单分子水平上更详细地对该系统进行系统研究。该提案有三个具体目标。第一个目标集中于阐明单个噬菌体基因组如何有助于裂解/溶原性决定。它包括探索细胞内的噬菌体DNA的时空信息如何与细胞命运相关，如何描述裂解/溶原性决定响应于已知的确定性因素（例如，感染细胞的数量和细胞大小）时，在单个噬菌体DNA水平上进行检查时得到改善，以及如何通过混合感染实验相互合作或竞争。第二个目标侧重于系统地确定裂解/溶原性在全谱不同生长条件和噬菌体因子下的灵敏度和响应性，并采用高分辨率和高通量方法研究基因表达。最后的目的是开发数学和计算模型的基因表达，占噬菌体复制，解释各种遗传和环境因素的影响裂解/溶原性的决定。总的来说，我们的希望是达到一个定量的了解如何各种确定性因素和随机性有助于一个众所周知的，但不完全理解的发展过程的结果。