Spatiotemporal modeling of signal transduction in yeast

酵母信号转导的时空模型

• 批准号: 8537930
• 负责人: Timothy C Elston
• 金额: $ 32.76万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2014-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8537930
• 关键词: Address; Biochemical Genetics; Biological Process; Cell Polarity; Cells; Complex; Computer Analysis; Development; Devices; Dose; Endocytosis; Environment; Eukaryota; Eukaryotic Cell; Event; Experimental Designs; Frequencies; GTP-Binding Protein Regulators; GTP-Binding Proteins; Genetic Techniques; Goals; Growth; Hormones; Human; Investigation; Lead; MAP Kinase Modules; Measurement; Methods; Microfluidic Microchips; Mitogen-Activated Protein Kinase Kinases; Modeling; Morphogenesis; Morphology; Neurotransmitters; Organism; Partner in relationship; Pathway interactions; Pheromone; Play; Proteins; Research; Role; Saccharomyces cerevisiae; Sensory; Signal Transduction; Signaling Molecule; Site; Testing; Time; Yeast Model System; Yeasts; base; environmental change; experimental analysis; human disease; improved; interdisciplinary approach; mathematical model; migration; mutant; novel; novel strategies; predictive modeling; programs; prototype; public health relevance; receptor; research study; response; spatiotemporal

DESCRIPTION (provided by applicant): The ability to detect and respond to spatial gradients of signaling molecules is fundamental for many biological processes in eukaryotic cells, such as differentiation, migration and morphogenesis. While much is known about the proteins that are required for signal transduction and gradient sensing, the precise mechanism by which they interact to transmit information about the environment and create internal gradients of protein activity remain unclear. This proposal seeks to establish the role of receptor endocytosis in modulating signaling activity and gradient sensing in the mating response of Saccharomyces cerevisiae (yeast). Yeast undergo a developmental decision based on the concentration of pheromone. At high pheromone levels, they growth arrest and generate a mating projection ("shmoo" morphology). At intermediate concentrations they elongate in the direction of an increasing pheromone gradient (chemotrophic growth). This decision requires that the mating response pathway transmit quantitative information about the external pheromone concentration. Through a combination of mathematical modeling and experimental analysis we accumulated strong evidence to support the idea that information about pheromone concentration is transmitted not as the amplitude of signal activity but as signal duration. One goal of this proposal is to test the hypothesis that receptor endocytosis plays an important role in this "dose-to-duration" conversion. Several experimental and theoretical investigations have suggested that receptor endocytosis is important for establishing cell polarity. Recent theoretical investigations also have suggested that receptor endocytosis increase cell's ability to detect external gradients of signaling molecules. A second goal is to test the hypothesis that receptor endocytosis increases yeast's ability to detect pheromone gradients and track gradients that change in time. The specific aims are: Aim 1. Characterize the role of receptor endocytosis in modulating signal activity. This aim tests the hypothesis that receptor endocytosis provides a mechanism for dose-to-duration encoding. Mathematical modeling is combined with experimental approaches to compare signal activity and responses in wild-type and defined mutant strains of yeast. Aim 2. Characterize the role of receptor endocytosis in gradient sensing. This aim uses mathematical and experimental approaches to test the hypothesis that receptor endocytosis increases yeast's ability to detect a pheromone gradient. Aim 3. Characterize yeast's ability to respond to changing external conditions. This aim tests the hypothesis that receptor endocytosis allows yeast to track time-dependent pheromone gradients. Our recent development of a microfluidics device that allows the direction of a gradient to be modulated in time is a critical feature of our experimental design for investigating yeast's ability to track changing environmental conditions.

描述（由申请人提供）：检测和响应信号分子空间梯度的能力是真核细胞中许多生物过程的基础，例如分化、迁移和形态发生。尽管人们对信号转导和梯度传感所需的蛋白质了解很多，但它们相互作用以传输环境信息并产生蛋白质活性内部梯度的精确机制仍不清楚。该提案旨在确定受体内吞作用在调节酿酒酵母（酵母）交配反应中的信号活动和梯度传感中的作用。酵母根据信息素的浓度做出发育决定。在高信息素水平下，它们生长停滞并产生交配投射（“shmoo”形态）。在中等浓度下，它们沿着信息素梯度增加的方向伸长（趋化生长）。这一决定要求交配反应途径传输有关外部信息素浓度的定量信息。通过数学建模和实验分析的结合，我们积累了强有力的证据来支持以下观点：信息素浓度的信息不是以信号活动的幅度而是以信号持续时间的形式传输的。该提案的一个目标是检验受体内吞作用在这种“剂量到持续时间”转换中发挥重要作用的假设。一些实验和理论研究表明受体内吞作用对于建立细胞极性很重要。最近的理论研究还表明，受体内吞作用增加了细胞检测信号分子外部梯度的能力。第二个目标是检验这样的假设：受体内吞作用增加了酵母检测信息素梯度和跟踪随时间变化的梯度的能力。具体目标是： 目标 1. 表征受体内吞作用在调节信号活性中的作用。该目的检验了受体内吞作用提供了剂量-持续时间编码机制的假设。数学模型与实验方法相结合，比较野生型和特定突变型酵母菌株的信号活性和反应。目标 2. 表征受体内吞作用在梯度传感中的作用。该目标使用数学和实验方法来检验受体内吞作用增加酵母检测信息素梯度的能力的假设。目标 3. 表征酵母响应不断变化的外部条件的能力。该目的测试了受体内吞作用允许酵母追踪时间依赖性信息素梯度的假设。我们最近开发的微流体装置可以及时调节梯度方向，这是我们研究酵母跟踪环境条件变化能力的实验设计的一个关键特征。