Molecular mechanism of general stress signaling in Brucella abortus

流产布鲁氏菌一般应激信号传导的分子机制

基本信息

批准号：
8793743
负责人：
Sean Crosson
金额：
$ 43.98万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8793743
关键词：
Address Affect Affinity Agriculture Animals Bacteria Binding Binding Sites Biochemical Biochemistry Biological Biophysics Brucella Brucella abortus Brucellosis Cells Cellular biology Chemicals Chicago Chronic Chronic Phase Computing Methodologies Containment Cues Data Detection Disease Environment Flavins Gene Expression Genetic Genetic Transcription Goals Growth Harvest Health Human In Vitro Infection Investigation Laboratories Measures Modeling Molecular Mus N-terminal Peptide Hydrolases Phosphorylation Phosphotransferases Positioning Attribute Postdoctoral Fellow Proteins Proteobacteria Proteolysis Regulation Research Resistance Role Sensory Signal Pathway Signal Transduction Stress Stress Response Signaling Structure System Testing Tissues Transcriptional Activation Transcriptional Regulation Universities Virulence Work base biodefense biological adaptation to stress experience genetic regulatory protein global health in vivo novel pathogen pathogenic bacteria programs protein function protein-histidine kinase reconstitution release factor research study residence response sensor sensor histidine kinase spatiotemporal stressor yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): The goal of this research program is to develop a mechanistic understanding of the general stress response (GSR) signaling system in the select agent pathogen, Brucella abortus. Our preliminary data demonstrate that this signaling system controls environmental stress adaptation and chronic infection in a mammalian infection model. B. abortus GSR signaling is controlled in part by the PhyR protein, a conserved regulator of adaptation to environmental stress that is broadly conserved in the ¿-proteobacterial clade. PhyR contains an amino terminal ECF ¿-like domain and a carboxy-terminal TCS receiver domain. Phosphorylation activates PhyR as an anti-anti-¿ factor and releases the classical ECF ¿ factor, ¿E1 to directly regulate gene expression during stress. Our multi-disciplinary investigation of PhyR, ¿E1 and other components of the GSR signaling system will define the mechanistic underpinnings of general stress signaling in a pathogen of significant human health, agricultural, and biodefense import. Moreover, the experiments proposed herein have the potential to inform new treatments for ¿-proteobacterial disease such as brucellosis. As mentioned above, this proposal is highly multi-disciplinary, spanning genetics, biochemistry, molecular biophysics, cell biology, and whole-animal infection studies. I will conduct these studies with a team of three experienced postdoctoral fellows, all of whom have expertise working on this BSL3 select agent in containment at the University of Chicago Howard Taylor Ricketts Regional Biocontainment Laboratory. The specific aims of this project are: 1) Define the role of the sensor histidine kinase, LovhK, as a GSR stress sensor, and characterize the molecular basis of stress signal detection by LovhK. 2) Define signals that activate the B. abortus general stress response in vitro and in a mammalian infection model. 3) Elucidate the structural mechanism of GSR activation.

描述（由申请人提供）：本研究项目的目标是对选定的病原体流产布鲁氏菌的一般应激反应（GSR）信号系统有一个机制上的了解。我们的初步数据表明，该信号系统控制着环境应激适应。哺乳动物感染模型中的慢性感染和流产 B. abortus GSR 信号传导部分由 PhyR 蛋白控制，PhyR 蛋白是一种在环境应激中广泛保守的保守调节因子。 -变形菌分支 PhyR 包含氨基末端 ECF ¿ - 样结构域和羧基末端 TCS 受体结构域，磷酸化可激活 PhyR 作为抗抗 ¿因子并释放经典 ECF ¿因素， E1 在应激过程中直接调节基因表达我们对 PhyR 的多学科研究，¿ E1和GSR信号系统的其他组成部分将定义对人类健康、农业和生物防御具有重要意义的病原体中一般应激信号传导的机制基础。此外，本文提出的实验有可能为疾病的新治疗提供信息。 -布鲁氏菌病等变形菌病。如上所述，该提案是高度多学科的，涵盖遗传学、生物化学、分子生物物理学、细胞生物学和全动物感染研究。我将与三名经验丰富的博士后研究员组成的团队进行这些研究。，所有这些人都拥有在芝加哥大学 Howard Taylor Ricketts 区域生物防护实验室从事 BSL3 选择隔离剂工作的专业知识。该项目的具体目标是： 1) 定义角色。传感器组氨酸激酶 LovhK 作为 GSR 应激传感器，并描述 LovhK 应激信号检测的分子基础 2) 定义在体外和哺乳动物感染模型中激活流产布鲁氏菌一般应激反应的信号 3)。阐明GSR激活的结构机制。