Mechanisms of noise regulation in cell fate transitions

细胞命运转变中的噪声调节机制

• 批准号: 9059133
• 负责人: Henrik G. Dohlman
• 金额: $ 52.39万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9059133
• 关键词: Address; Affect; Age; Aging; Animal Model; Behavior; Biological; Biological Models; Birth; Cell Aging; Cell Cycle; Cell Surface Receptors; Cell physiology; Cells; Characteristics; Computer Simulation; Controlled Environment; Cues; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; Engineering; Eukaryota; G-Protein Signaling Pathway; GTP-Binding Protein Regulators; GTP-Binding Proteins; Gene Expression; Genetic; Growth; Health; Heterogeneity; Hormones; Human; Image Analysis; Individual; Investigation; Learning; Logic; MAP Kinase Gene; MAP Kinase Modules; Malignant Neoplasms; Measures; Mediating; Methods; Microfluidic Microchips; Microfluidics; Mitogen-Activated Protein Kinases; Mitotic; Modeling; Molecular; Monitor; Mutation; Neurotransmitters; Noise; Nutrient; Organism; Partner in relationship; Pathway interactions; Peptides; Pharmacology; Pheromone; Physiology; Population; Process; Proliferating; Property; Regulation; Reporter; Research; Research Personnel; Resistance; Role; Shapes; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Source; Sterility; Stimulus; Stress; System; Testing; Time; Transcriptional Regulation; Work; Yeasts; age related; base; chemotherapy; cyclin G1; environmental change; fluorescence imaging; mathematical model; mutant; prototype; quantitative imaging; response; senescence; success; tool; tumor

 DESCRIPTION (provided by applicant): Cellular behavior is controlled by environmental signals including nutrients, osmotic stress, hormones and neurotransmitters. Only recently have investigators begun to address how the response to any of these stimuli varies from cell to cell. This project focuses on mechanisms of noise regulation in cellular signal transduction and their role in determining cell fate. Our investigation exploits a prototype G protein signaling pathway in yeast. In this system, a peptide mating pheromone activates a cell surface receptor, a G protein, and a MAP kinase signaling cascade. Our recent work revealed that several pathway components act in a dynamic manner to regulate the time-dependent noise characteristics of the pathway. This observation motivated our primary hypothesis that the sources of noise responsible for cell-to-cell variability are regulated to promote cellular survival under changing environmental conditions. In certain contexts, fluctuations may serve as "bet-hedging" mechanisms to diversify the response of a population of isogenic cells, whereas in other contexts noise suppression may be required to properly coordinate response pathways when cells are faced with multiple competition stimuli. Our research plan uses microfluidic devices and fluorescent imaging to follow single cells in well controlled environments, quantitative image analysis to characterize fluctuations in signaling and gene expression, and stochastic modeling to suggest and test noise regulation mechanisms. The following aims will be used to determine the role of noise in shaping cellular behavior and identify the biological circuits that regulate is properties: Aim 1 analyzes effects of noise on the cellular decision to differentiate or proliferat. Aim 2 analyzes mechanisms of noise suppression required for coordination between two MAP kinase pathways, one that promotes differentiation and one that is required for adaptation to osmotic stress. Aim 3 analyzes effects of noise in the transition to age-dependent sterility. Our findings will reveal the organization and logic of signaling circuits that regulate noise and to wht extent noise influences cell fate decisions and survival. Such systems level principles are likely to be shared by many signal pathways in organisms ranging from yeast to humans. Yeast is an ideal platform for these analyses; all of the cells in the population are genetically identical, an can be maintained under uniform and easily modulated growth conditions. Genetic manipulability is unparalleled and the consequences of any changes are easily quantified. Thus it is practical to modulate noise by genetic or environmental changes, measure the functional consequences, develop computational models and test them experimentally. This integrated approach is ideal for both hypothesis-generating and hypothesis- testing. Finally, the signaling pathway in yeast employs cell-surface receptors, G proteins, MAP kinases, and cyclin dependent kinases (CDKs) homologous to those found in humans. Thus signaling mechanisms identified in yeast will inform human physiology and pharmacology.

 描述（通过应用程序提供）：细胞行为由养分，渗透应激，骑马和神经递质在内的环境信号控制。直到最近，研究者才开始解决从细胞到细胞的任何刺激变化中对这些刺激的任何一种的反应。该项目的重点是细胞信号转导中噪声调节的机制及其在确定细胞命运中的作用。我们的投资利用了酵母中原型G蛋白信号通路。在该系统中，肽交配信息素激活细胞表面受体，G蛋白和MAP激酶信号传导级联反应。我们最近的工作表明，几个途径成分以动态方式起作用以调节途径的时间依赖性噪声特征。这一观察结果激发了我们的主要假设，即负责细胞对细胞变异性的噪声来源以促进环境条件下的细胞存活。在某些情况下，波动可能是“围攻”机制，以多样化等源细胞的响应，而在其他情况下，当细胞面临多个竞争刺激时，可能需要噪声抑制才能正确地协调响应途径。我们的研究计划使用微流体设备和荧光成像在良好的控制环境中跟随单个细胞，定量图像分析来表征信号传导和基因表达中的波动，以及随机建模以暗示和测试噪声调节机制。以下目的将用于确定噪声在塑造细胞行为中的作用，并确定调节特性的生物回路：AIM 1分析噪声对分化或增殖的细胞决策的影响。 AIM 2分析了两种MAP激酶途径之间需要协调所需的噪声抑制机制，该途径促进了分化，而一种适应渗透应激所需的分化。 AIM 3分析噪声在过渡到年龄依赖性的无菌性中的影响。我们的发现将揭示信号电路的组织和逻辑，这些信号电路调节噪声以及噪声在多大程度上影响细胞命运的决策和生存。从酵母到人类的生物中，许多信号途径可能会共享此类系统级别原理。酵母是这些分析的理想平台；人群中的所有细胞在遗传上都是相同的，一个可以维持在均匀且易于调节的生长条件下。遗传可操作性是无与伦比的，任何变化的后果都很容易量化。通过遗传或环境变化来调节噪声是实际的，测量功能后果，开发计算模型并通过实验测试它们。这种综合方法是假设生成和假设检验的理想选择。最后，酵母员工细胞表面受体，G蛋白，MAP激酶和细胞周期蛋白依赖性激酶（CDKS）的信号传导途径与人类发现的激酶（CDKS）同源。在酵母中鉴定出的信号传导机制将为人类的生理学和药理学提供信息。