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）：当被细菌病原体感染时，人类细胞会产生活性氧。这种氧化爆发旨在杀死潜在的入侵者。已经表征了几种细菌转录因子，这些因子对活性氧反应以控制基因表达并防御这种氧化爆发。还已经表明，对宿主衍生的活性氧的细菌反应效率低下可降低感染性。因此，了解人类健康非常重要，以便能够施用有效的抗微生物剂。在该程序中，我们专注于氧化爆发的相关方面，即尿酸盐的伴随产生。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，可将低黄嘌呤转化为黄嘌呤和木氨酸，从而将其转化为尿酸盐。 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多种抗生素耐药性调节剂（MARR）家族。我们计划使用泰国人的Burkholderia thailandensis作为模型系统，我们计划确定该转录因子对DNA结合的DNA结合的机理，以及在其控制下的调节机理，我们计划确定对氧化应激的响应依赖紫外的转录调节。所提出的实验计划将扩展已知的机制，该机制通过响应氧化应激而调节基因表达以及对宿主 - 病原体相互作用的相关潜力的相关潜力，并且它将提供一个将学生暴露于生物医学研究的环境。