System Dynamics of the Salmonella Virulence Regulatory Network
沙门氏菌毒力监管网络的系统动力学
基本信息
- 批准号:7547733
- 负责人:
- 金额:$ 29.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-01-01 至 2011-12-31
- 项目状态:已结题
- 来源:
- 关键词:AnimalsBacteriaBinding SitesBiochemicalBiological ModelsBordetellaCellsChlamydiaCommitComplexComputing MethodologiesCuesCytosolDevelopmentDevicesEngineeringEscherichia coliFeedbackGene ExpressionGenesGeneticGenetic RecombinationHealthHumanIn VitroIndividualInternetInvadedKnowledgeLeadLibrariesLinkLogicMammalian CellMeasuresMessenger RNAMethodsMolecularMutagenesisNeedlesPathway interactionsPlantsProcessPropertyProteinsPseudomonasRegulationRegulator GenesRegulatory PathwayResearchResearch PersonnelRibosomesSalmonellaShigellaSignal TransductionStimulusStructural GenesStructureSyringesSystemTestingTherapeuticType III Secretion System PathwayVirulenceWorkYersiniabasedesigngenetic regulatory proteininsightlambda Spi-1mathematical modelnew therapeutic targetnovelpathogenpractical applicationprogramspromoterprotein expressionresearch studyresponseself assemblytheoriestranscription factorvaccine delivery
项目摘要
Cells rely on complex regulatory networks to sense and respond to environmental cues. The dynamics of the
regulatory network governing cellular responses cannot be understood at the level of individual regulatory
proteins, but rather emerges as a result of a complex web of biochemical interactions between multiple
proteins, mRNA, and DMA. Our long-term objective to develop computational and experimental methods to
dissect and analyze regulatory networks. With respect to human health, one of the most important
prokaryotic regulatory networks underlies the type III secretion system (TTSS). The TTSS acts like a
molecular syringe to inject bacterial effector proteins into the host cytosol. The TTSS is critical for virulence
for many gram-negative pathogens, including Salmonella, Pseudomonas, E. coli, Shigella, Yersinia,
Chlamydia, and Bordetella. Of these, the Salmonella TTSS responsible for invading mammalian cells (SPI-1)
has the most well-characterized structure and regulation and is the focus of this proposal.
In preliminary experiments, we have observed: 1. there is a temporal order in the expression of SPI-1
genes, 2. there is independent control of structural and effector genes, 3. there is hysteresis in the
expression of effectors, and 4. the stochastic component of gene expression is differentially controlled.
Based on these experiments, we hypothesize that the dynamics are dictated by two genetic circuits in the
pathway. The first acts like a multi-signal integrator that commits to SPI-1 expression. The second is a
bistable switch, where effectors are irreversibly activated after the needle structure is completed. This
proposal seeks to use a combination of experiments, theory, and engineering to quantitatively characterize
these circuits.
Aim 1: Characterize two genetic circuits in the SPI-1 regulatory pathway. The first is responsible for
integrating many environmental inputs and committing to the expression of the TTSS. The second forms a
bistable switch that causes effector expression to persist after the input stimulus is removed.
Aim 2: Engineer the network dynamics by adding artificial feedback loops. To determine how the topology of
regulatory interactions encodes network dynamics, artificial feedback loops will be used to genetically
perturb the network. This will provide insight into how complex dynamics evolve.
细胞依靠复杂的调节网络来感知和响应环境信号。的动态
控制细胞反应的调节网络不能在个体调节水平上理解。
蛋白质,而是作为多种生物化学相互作用的复杂网络的结果出现。
蛋白质、mRNA和DNA。我们的长期目标是发展计算和实验方法,
剖析和分析监管网络。关于人类健康,最重要的
原核调节网络是III型分泌系统(TTSS)的基础。TTSS就像一个
分子注射器将细菌效应蛋白注入宿主细胞质。TTSS对毒力至关重要
对许多革兰氏阴性病原体,包括沙门氏菌、假单胞菌、E.大肠杆菌,志贺氏菌,耶尔森氏菌,
衣原体和博德特氏菌。其中,沙门氏菌TTSS负责入侵哺乳动物细胞(SPI-1)
具有最具特色的结构和监管,是本提案的重点。
在初步实验中,我们观察到:1。SPI-1的表达有时间顺序
基因,2.结构基因和效应基因的独立控制; 3.存在滞后,
效应子的表达,以及4.基因表达的随机成分受到差异控制。
基于这些实验,我们假设这种动力学是由大脑中的两个遗传回路决定的。
通路第一个类似于提交SPI-1表达式的多信号积分器。第二个是
触发开关,其中效应器在针结构完成后被不可逆地激活。这
一项提案寻求使用实验、理论和工程相结合的方法来定量表征
这些电路。
目的1:描述SPI-1调控通路中的两个遗传回路。第一是负责
整合多种环境投入,致力于TTSS的表达。第二种形式是a
在输入刺激被去除后,使效应器表达持续的一种开关。
目标2:通过添加人工反馈回路来设计网络动态。要确定
监管相互作用编码网络动态,人工反馈回路将用于遗传
扰乱网络。这将提供对复杂动态如何演变的洞察。
项目成果
期刊论文数量(0)
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CHRISTOPHER A VOIGT其他文献
CHRISTOPHER A VOIGT的其他文献
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{{ truncateString('CHRISTOPHER A VOIGT', 18)}}的其他基金
A Toolkit for Light-Control of Molecular Processes in Living Cells
活细胞中分子过程的光控制工具包
- 批准号:
8237893 - 财政年份:2012
- 资助金额:
$ 29.3万 - 项目类别:
System Dynamics of the Salmonella Virulence Regulatory Network
沙门氏菌毒力监管网络的系统动力学
- 批准号:
8524180 - 财政年份:2012
- 资助金额:
$ 29.3万 - 项目类别:
A Toolkit for Light-Control of Molecular Processes in Living Cells
活细胞中分子过程的光控制工具包
- 批准号:
8431348 - 财政年份:2012
- 资助金额:
$ 29.3万 - 项目类别:
A Toolkit for Light-Control of Molecular Processes in Living Cells
活细胞中分子过程的光控制工具包
- 批准号:
8616764 - 财政年份:2012
- 资助金额:
$ 29.3万 - 项目类别:
A Toolkit for Light-Control of Molecular Processes in Living Cells
活细胞中分子过程的光控制工具包
- 批准号:
8811136 - 财政年份:2012
- 资助金额:
$ 29.3万 - 项目类别:
Characterization of Gradient-Responsive Genetic Programs Using Light Sensors
使用光传感器表征梯度响应遗传程序
- 批准号:
8022971 - 财政年份:2011
- 资助金额:
$ 29.3万 - 项目类别:
Characterization of Gradient-Responsive Genetic Programs Using Light Sensors
使用光传感器表征梯度响应遗传程序
- 批准号:
8386775 - 财政年份:2011
- 资助金额:
$ 29.3万 - 项目类别:
Characterization of Gradient-Responsive Genetic Programs Using Light Sensors
使用光传感器表征梯度响应遗传程序
- 批准号:
8403398 - 财政年份:2011
- 资助金额:
$ 29.3万 - 项目类别:
Characterization of Gradient-Responsive Genetic Programs Using Light Sensors
使用光传感器表征梯度响应遗传程序
- 批准号:
8599474 - 财政年份:2011
- 资助金额:
$ 29.3万 - 项目类别:
Characterization of Gradient-Responsive Genetic Programs Using Light Sensors
使用光传感器表征梯度响应遗传程序
- 批准号:
8207214 - 财政年份:2011
- 资助金额:
$ 29.3万 - 项目类别:
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