An Integrative Analysis of MAPK Signaling in Budding Yeast

芽殖酵母中 MAPK 信号传导的综合分析

基本信息

批准号：
7446864
负责人：
Andre Levchenko
金额：
$ 33.46万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-10 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7446864
关键词：
Behavior Control Cell Communication Cells Cellular Morphology Characteristics Collection Complex Computer Simulation Devices Disease Dose Environment Eukaryota Eukaryotic Cell Event Experimental Designs Feedback Gene Expression Genes Genetic Genetic Programming Genetic Transcription Green Fluorescent Proteins Growth Haploid Cells Health Human Human Pathology Imagery Knowledge Life Mediating Mediator of activation protein Microfluidic Microchips Mitogen-Activated Protein Kinases Modeling Molecular Molecular Biology Morphogenesis Movement Mutation Organism Osmolar Concentration Output Partner in relationship Pathway Analysis Pathway interactions Phenotype Pheromone Physiological Process Public Health Regulation Research Role Saccharomyces cerevisiae Saccharomycetales Scaffolding Protein Screening procedure Signal Pathway Signal Transduction Signal Transduction Pathway Sorbitol Structure System Systems Biology Technology Testing Time Work Yeasts cell behavior cell growth insight interest next generation novel novel strategies prototype research study response tool

项目摘要

DESCRIPTION (provided by applicant): The mating response pathway regulating fusion of two haploid cells of the budding yeast S. cerevisiae or activated in response to exogenously added pheromones has been a prototypical signal transduction pathway, whose analysis led to multiple important insights into the structure and function of mitogen-activated protein kinase (MAPK) cascades. A vast collection of genetic and molecular biology tools have been developed that continue to make this pathway a very attractive system for developing a progressively refined understanding of how the signals from the cell microenvironment are converted into well defined changes in gene transcription and cell morphology. However, our understanding of this important pathway is far from complete, in large part due to the lack of experimental tools for analysis of the pathway activity in more physiological contexts of gradient sensing and chemotropism, and the sequential projection formation in saturating pheromone gradients (the default response), as opposed to the relatively short term responses to spatially homogeneous pheromone concentrations. In this application, we propose to study the mating pathway within the contexts of gradient sensing and default response phenotypes using novel experimental designs and microfabricated devices. We propose to investigate the role of various modifiers of pathway activity, with a particular focus on the scaffold protein and various negative regulators. We will also explore the mechanisms of cross-talk between the pheromone pathway and other MAPK pathways, also relying on the novel experimental technology. The results of these quantitative experimental analyses will be integrated into a comprehensive computational model of the MAPK pathways activated in budding yeast. Conservation of MAPK pathways across species and the particular importance of these pathways in various human pathologies make this research especially significant for our understanding of human health and disease. PUBLIC HEALTH RELEVANCE: This application is focused on the systems approach to signal transduction in one of the prototypical and most studied pathways, the mating pathway in yeast. In spite of its apparent simplicity, this pathway regulates a plethora of cell responses, from changes in cell morphology and directed cell growth, to periodic morphogenesis and expression of hundreds of genes. We propose using a set of novel approaches to investigate the way the pathway can control this diverse set of phenotypic responses and build a quantitative understanding of the pathway function. We anticipate that our findings will be informative about the function of other pathways in yeast and higher organisms.

描述（由申请人提供）：调节酿酒酵母的两个单倍体细胞的融合的交配响应途径是一种原型信号传递途径，其分析导致对Mitit蛋白蛋白基因酶（Mapk）的结构和功能的多个重要见解。已经开发了大量的遗传和分子生物学工具，该工具继续使该途径成为非常有吸引力的系统，以逐步完善对细胞微环境信号如何转化为基因转录和细胞形态的良好变化的信号。但是，我们对这一重要途径的理解远非完整，这在很大程度上是由于缺乏实验性工具来分析梯度传感和趋化性的更生理环境中的途径活性，以及在饱和的信息素梯度（默认响应）中的顺序投影形成（默认响应），而不是相对短期对空间同型同型浓度相对较短的响应。在此应用程序中，我们建议在梯度传感和默认响应表型中使用新型的实验设计和微制设备研究交配途径。我们建议研究途径活性的各种修饰符的作用，特别关注支架蛋白和各种负调节剂。我们还将探讨信息素通路和其他MAPK途径之间的跨话的机制，这也依赖于新型的实验技术。这些定量实验分析的结果将集成到在发芽酵母中激活的MAPK途径的综合计算模型。跨物种的MAPK途径的保护以及各种人类病理中这些途径的特殊重要性使得这项研究对我们对人类健康和疾病的理解特别重要。公共卫生相关性：该应用集中在系统的方法上，以发出典型且研究最多的途径之一，即酵母的交配途径。尽管具有明显的简单性，但该途径仍调节了许多细胞反应，从细胞形态和定向细胞生长的变化到定期形态发生和数百个基因的表达。我们建议使用一组新型方法来研究途径可以控制这组表型响应的方式，并对途径功能建立定量理解。我们预计我们的发现将使其他途径在酵母和更高生物体中的功能有所帮助。