An Integrative Analysis of MAPK Signaling in Budding Yeast

芽殖酵母中 MAPK 信号传导的综合分析

• 批准号: 7609111
• 负责人: Andre Levchenko
• 金额: $ 30.86万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/7609111
• 关键词: Behavior Control; Cell Communication; Cells; Cellular Morphology; Characteristics; Collection; Complex; Computer Simulation; Devices; Disease; Dose; Environment; Eukaryota; Event; Experimental Designs; Feedback; Gene Expression; Genes; Genetic; Genetic Programming; Genetic Transcription; 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; 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; public health relevance; research study; response; tool

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）：调节出芽酵母S. cerevisiae的两个单倍体细胞融合或响应外源添加的信息素而激活的交配反应途径是一个典型的信号转导途径，其分析导致了对丝裂原活化蛋白激酶（MAPK）级联的结构和功能的多个重要见解。大量的遗传和分子生物学工具已经被开发出来，这些工具继续使这一途径成为一个非常有吸引力的系统，用于开发对细胞微环境信号如何转化为基因转录和细胞形态中明确定义的变化的逐步完善的理解。然而，我们对这一重要途径的理解还远未完成，这在很大程度上是由于缺乏实验工具来分析在梯度传感和趋化性等生理背景下的途径活性，以及在饱和信息素梯度（默认反应）中形成的顺序投影（默认反应），而不是对空间均匀信息素浓度的相对短期反应。在这个应用中，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反应表型背景下的交配途径。我们建议研究各种途径活性调节剂的作用，特别关注支架蛋白和各种负调节因子。我们还将依靠新的实验技术，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出芽酵母中激活的MAPK途径的综合计算模型中。跨物种的MAPK通路的保护以及这些通路在各种人类病理中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：本应用侧重于信号转导的系统方法，这是酵母中最典型和研究最多的途径之一，即交配途径。尽管它看起来很简单，但这种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，到数百个基因的周期性形态发生和表达。我们建议使用一套新颖的方法来研究该途径如何控制这种多样化的表型反应，并建立对该途径功能的定量理解。我们预计我们的发现将对酵母和高等生物中其他途径的功能提供信息。