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Bacterial gene regulation in response to oxidative stress

细菌响应氧化应激的基因调控

基本信息

批准号：
8574250
负责人：
ANNE GROVE
金额：
$ 31.79万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8574250
关键词：
Address Anabolism Anti-Bacterial Agents Antibiotic Resistance Antioxidants Attenuated Bacteria Bacterial Genes Bacterial Infections Binding Biological Models Biomedical Research Burkholderia Cells DNA Binding Defense Mechanisms Environment Enzymes Event Family Gene Expression Gene Expression Regulation Generations Genes Goals Health Homologous Gene Human Hypoxanthines In Vitro Intervention Invaded Ligands Mammalian Cell Mediating Names Oxidative Stress Plants Production Protein Family Purines Reactive Oxygen Species Regulon Reporting Respiratory Burst Role Signal Transduction Signaling Molecule Students Tissues Transcriptional Regulation Urate Virulence Work Xanthine Oxidase Xanthines antimicrobial antimicrobial drug attenuation base biological adaptation to stress derepression efflux pump in vivo interest killings member novel pathogen programs public health relevance purine response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Human cells produce reactive oxygen species when infected by a bacterial pathogen. This oxidative burst is intended to kill the would-be invader. Several bacterial transcription factors have been characterized that respond to reactive oxygen species to control gene expression and mount a defense against this oxidative burst. It has also been shown that an inefficient bacterial response to host-derived reactive oxygen species reduces infectivity. It is therefore of importance to human health to understand the full spectrum of host-pathogen interactions to be able to administer effective antimicrobial agents. In this program, we focus on a related aspect of the oxidative burst, namely the concomitant production of urate. Urate is produced because one of the two main enzymes responsible for production of reactive oxygen species is xanthine oxidase, which functions in purine degradation to convert hypoxanthine to xanthine and xanthine to urate. Based on our previous work in which we demonstrated that urate functions as a ligand for a transcription factor encoded by plant pathogens to mediate gene regulation, we now focus on two specific hypotheses: 1-That urate functions as a signaling molecule to effect gene regulation in certain bacterial species that are important human pathogens, and 2- that urate-mediated gene regulation is effected by a subset of transcriptional regulators that belong to the Multiple Antibiotic Resistance Regulator (MarR) family. Using Burkholderia thailandensis as a model system, we plan to identify the mechanism of urate-mediated attenuation of DNA binding by this transcription factor as well as the regulon under its control, and we plan to determine the role of urate-dependent transcriptional regulation in response to oxidative stress. The proposed experimental plan will extend the known mechanisms by which gene expression is regulated in response to oxidative stress with the associated potential for a deeper understanding of host-pathogen interactions, and it will furnish an environment in which students will be exposed to biomedical research.

描述（由申请人提供）：人体细胞被细菌病原体感染时会产生活性氧。这种氧化爆发的目的是杀死潜在的入侵者。一些细菌转录因子已被鉴定为对活性氧作出反应，以控制基因表达并对这种氧化爆发进行防御。研究还表明，细菌对宿主衍生的活性氧的低效反应会降低感染性。因此，了解宿主-病原体相互作用的全谱，以便能够施用有效的抗菌药物，对人类健康至关重要。在这个节目中，我们关注氧化爆发的一个相关方面，即伴随的尿酸盐的产生。产生尿酸盐是因为负责产生活性氧的两种主要酶之一是黄嘌呤氧化酶，它在嘌呤降解中起作用，将次黄嘌呤转化为黄嘌呤，将黄嘌呤转化为尿酸盐。基于我们之前的工作，我们证明了尿酸盐作为植物病原体编码的转录因子的配体来介导基因调控，我们现在专注于两个特定的假设：1-尿酸盐作为一种信号分子，在某些重要的人类病原体细菌物种中发挥基因调控的作用，2-尿酸盐介导的基因调控受多种抗生素耐药调节剂（MarR）家族的转录调控子的影响。以泰国伯克霍尔德氏菌为模型系统，我们计划确定该转录因子尿酸盐介导的DNA结合衰减机制及其调控的调控子，并计划确定其作用