Modeling Feedback Regulation of Cell Signaling

细胞信号传导反馈调节建模

• 批准号: 8118352
• 负责人: Henrik G. Dohlman
• 金额: $ 10.79万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118352
• 关键词: Behavior; Biological; Cell Surface Receptors; Cell membrane; Cell physiology; Cells; Characteristics; Chemotaxis; Complex; Computer Analysis; Computer Simulation; Cues; Detection; Dose; Eukaryota; Event; Feedback; GTP-Binding Proteins; Growth; Guanosine Triphosphate Phosphohydrolases; Hormones; Human; Lead; MAP Kinase Modules; Measures; Mitogen-Activated Protein Kinases; Modeling; Molecular; Neurotransmitters; Nutrient; Organism; Pathway interactions; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pheromone; Phosphorylation; Production; Protein Kinase; Proteins; RGS Proteins; Regulation; Role; Scaffolding Protein; Signal Transduction; Site; Stimulus; Stress; System; Techniques; Testing; Time; Translating; Work; Yeasts; behavior test; combat; experimental analysis; gene replacement; human disease; improved; innovation; mutant; protein activation; public health relevance; receptor; research study; response; success; transmission process

DESCRIPTION (provided by applicant): SUMMARY Cellular behavior is modulated by environmental signals including nutrients, osmotic stress, hormones and neurotransmitters. These signals can vary considerably in dose, duration, and directionality. This proposal seeks to (i) quantitatively measure the yeast pheromone response pathway, both in time and space, (ii) devise computational models that describe the observed behaviors, and (iii) test the validity of each model through further experimentation. The over-arching hypothesis is that mathematical techniques developed for studying dynamical systems can explain how pathway components interpret and translate spatial cues outside the cell to evoke appropriate responses inside the cell. The focus will be on proteins that modulate the time-dependent behaviors of the pheromone pathway in yeast, and in particular how these modulators contribute to proper signal transduction. Models will be tested experimentally at the molecular and cellular level, and include the use of an innovative gradient flow chamber. There are three specific aims, focused on three different proteins acting at three distinct steps in the pathway. All three proteins are required for gradient-sensing activity. Aim 1 will investigate time-dependent regulation by the scaffold protein Ste5. This aim will test the hypothesis that Ste5 modulates signaling by imposing a delay between each of two phosphorylation events needed for full activation of a MAP kinase Fus3. Aim 2 will investigate time- and space-dependent regulation by the RGS protein Sst2. This aim will test the hypothesis that Sst2 functions as a scaffold protein that coordinates G protein activation (by the receptor) and inactivation (of the G protein), and thereby orients the cell towards a gradient stimulus. Aim 3 will investigate time- and space-dependent regulation by the pheromone protease Bar1. This aim will test the hypothesis that Bar1 remodels the gradient, and thereby coordinates the behavior of two cells responding to the same stimulus. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Proper cell function requires the ability to detect and respond appropriately to hormones, neurotransmitters and drugs. The cellular machinery responsible for signal transmission is conserved from humans to yeast. This project uses multi-disciplinary approaches, including biological experiments, microfabricated growth chambers and computer simulations, to establish how the direction and strength of a stimulus are interpreted by the cell. The broader objective is to understand the role of spatial and temporal information in cell signaling, and eventually predict what drug treatments will be most effective in combating human diseases.

描述（由申请人提供）： 摘要的细胞行为受环境信号的调节，包括营养素，渗透应激，激素和神经递质。这些信号的剂量，持续时间和方向性可能会有很大差异。该提案试图（i）定量测量酵母信息素响应途径，无论是在时空和空间上，（ii）设计了描述观察到的行为的计算模型，（iii）通过进一步的实验来测试每个模型的有效性。总结的假设是，用于研究动态系统开发的数学技术可以解释路径组件如何解释和翻译细胞外的空间提示，以引起细胞内部的适当响应。重点将放在调节酵母中信息素途径的时间依赖性行为的蛋白质上，尤其是这些调节剂如何促进正确的信号转导。模型将在分子和细胞水平进行实验测试，并包括使用创新的梯度流动室。有三个特定的目标，集中在三种不同的蛋白质上，该蛋白在途径中的三个不同步骤上作用。所有三种蛋白质都是梯度感应活性所必需的。 AIM 1将研究脚手架蛋白Ste5的时间依赖性调节。该目标将检验以下假设，即Ste5通过在完全激活MAP激酶FUS3所需的两个磷酸化事件之间施加延迟来调节信号传导。 AIM 2将研究RGS蛋白SST2的时间和空间依赖性调节。该目的将检验以下假设：SST2充当支架蛋白，该蛋白会协调G蛋白激活（通过受体）和失活（G蛋白），从而将细胞朝向梯度刺激。 AIM 3将研究信息素蛋白酶BAR1的时间和空间依赖性调节。该目标将检验BAR1重塑梯度的假设，从而协调两个对相同刺激响应的细胞的行为。公共卫生相关性：项目叙事适当的细胞功能需要能够检测和对激素，神经递质和药物的适当反应。负责信号传输的细胞机械从人类到酵母菌保存。该项目使用多学科的方法，包括生物学实验，微生物生长室和计算机模拟，以确定细胞如何解释刺激的方向和强度。更广泛的目标是了解空间和时间信息在细胞信号传导中的作用，并最终预测哪种药物治疗将最有效地对抗人类疾病。