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）：调节芽殖酵母酿酒酵母两个单倍体细胞融合或响应外源添加信息素而激活的交配反应途径是一种典型的信号转导途径，其分析导致对该结构的多个重要见解和丝裂原激活蛋白激酶（MAPK）级联的功能。已经开发出大量的遗传和分子生物学工具，这些工具继续使该途径成为一个非常有吸引力的系统，用于逐步完善地理解来自细胞微环境的信号如何转化为基因转录和细胞形态的明确变化。然而，我们对这一重要途径的理解还远未完成，很大程度上是由于缺乏实验工具来分析梯度传感和趋化性的更多生理背景下的途径活性，以及饱和信息素梯度中的顺序投影形成（默认响应），而不是对空间均匀信息素浓度的相对短期响应。在本申请中，我们建议使用新颖的实验设计和微制造设备来研究梯度传感和默认响应表型背景下的交配途径。我们建议研究途径活性的各种修饰剂的作用，特别关注支架蛋白和各种负调节剂。我们还将依靠新颖的实验技术，探索信息素途径与其他 MAPK 途径之间的串扰机制。这些定量实验分析的结果将被整合到芽殖酵母中激活的 MAPK 途径的综合计算模型中。 MAPK 通路在物种间的保守性以及这些通路在各种人类病理学中的特殊重要性使得这项研究对于我们了解人类健康和疾病特别重要。公共健康相关性：本申请重点关注原型和研究最多的途径之一（酵母交配途径）中信号转导的系统方法。尽管其表面上很简单，但该途径调节了大量的细胞反应，从细胞形态的变化和定向细胞生长，到周期性形态发生和数百个基因的表达。我们建议使用一组新方法来研究该通路控制这组不同表型反应的方式，并建立对该通路功能的定量理解。我们预计我们的发现将为酵母和高等生物中其他途径的功能提供信息。