Form and Function of Tandem Duplicate Small RNA Molecules in Shigella dysenteriae

痢疾志贺氏菌串联重复小 RNA 分子的形式和功能

基本信息

批准号：
8574164
负责人：
ERIN R MURPHY
金额：
$ 44.55万
依托单位：
OHIO UNIVERSITY ATHENS
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：
2013-07-16 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8574164
关键词：
Achievement Antibiotic Resistance Antibiotics Attention Bacteria Biological Assay Cell division Communicable Diseases Computer Simulation Data Development Disease Dysentery Environment Equilibrium Foundations Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Goals Human Human body Incidence Infection Infection prevention Invaded Iron Knowledge Mediating Mentors Modeling Molecular Nutrient Pathogenesis Pathway interactions Pattern Phenotype Physiology Play Positioning Attribute Process Production RNA Regimen Regulation Research Role Shigella Shigella Infections Shigella boydii Shigella dysenteriae Shigella flexneri Small RNA Structure Students System Temperature Testing Therapeutic Training Training Programs Vaccines Virulence Water antimicrobial drug bacterial genetics base commensal microbes experience human disease innovation model development novel therapeutics pathogen pathogenic bacteria prevent public health relevance response skills

项目摘要

DESCRIPTION (provided by applicant): Shigellosis, a several diarrheal disease caused by infection with bacteria of the genus Shigella, remains endemic throughout the world. The global burden of shigellosis is due in part to the lack of a vaccine to prevent the infection and the lack of a universally safe and available antibiotic regimen to treat the infection. While the potential f using small RNA molecules (sRNAs) as models for, or targets of, RNA-based anti-Shigella therapeutics is promising, what is lacking is a comprehensive understanding of the role that sRNAs play in controlling Shigella physiology and pathogenesis. A necessary first step towards achieving the long-term goal of developing RNA-based antibiotics to treat shigellosis is to reveal the full extent to which sRNAs control the physiology and virulence of Shigella species. To this end, the overall objective of this study is to elucidate the role of newly identified duplicate sRNAs RyfA1 and RyfA2 in controlling the physiology and pathogenesis of S. dysenteriae. The central hypothesis being tested is that RyfA1 and RyfA2 are differentially produced under unique environmental conditions and modulate S. dysenteriae virulence by regulating the expression of distinct over-lapping sets of genes. This hypothesis will be tested by achieving the following specific aims: 1) identify the iron- and temperature-responsive factors regulating the production of RyfA1 and RyfA2; 2) elucidate the function of RyfA1 and RyfA2 by identifying the regulatory targets of each; and 3) determine the effect of RyfA1 and RyfA2, individually and in combination, on S. dysenteriae virulence. The proposed systematic characterization of duplicate sRNAs, RyfA1 and RyfA2, will contribute to answering fundamental questions in the fields of Shigella pathogenesis and bacterial sRNAs, contributions that will facilitate achievement of the long-term goal of developing therapeutics to treat shigellosis. The proposed study puts forth the innovative hypothesis that two sRNA molecules that share 95% sequence identity and a identical predicted structure have non-redundant functions. This hypothesis will be tested using a balanced approach of standard, student friendly, bacterial genetics and innovative high-tech assays. Student involvement in every step of the proposed study form the foundation of an innovative training program that will provide students with practical experience in the fields of bacterial pathogenesis and RNA-based regulation. The resulting combination of skills and experience will position students well to contribute to the rapidly advancing fields of ribo-regulation in pathogenic bacteria, commensal bacteria and eukaryotic systems.

描述（由申请人提供）：Shigellosis是一种由志贺氏菌属细菌感染引起的几种腹泻疾病，在世界范围内仍然流行。全球志贺病的负担部分是由于缺乏疫苗来防止感染和缺乏疫苗一种普遍安全且可用的抗生素治疗方案来治疗感染。虽然使用小的RNA分子（SRNA）作为基于RNA的抗辣椒氏菌疗法的模型的潜在F是有希望的，但缺乏对SRNA在控制志贺氏菌生理学和病原体中所起的作用的全面理解。实现建立基于RNA的抗生素以治疗志智能病的长期目标的必要第一步是揭示SRNA控制志贺氏菌物种的生理和毒力的全部程度。为此，这项研究的总体目的是阐明新确定的重复SRNA Ryfa1和Ryfa2在控制嗜动链霉菌的生理和发病机理中的作用。正在检验的中心假设是Ryfa1和Ryfa2是在独特的环境条件下差异化的，并通过调节独特的不同基因基因集的表达来调节dyensenteriae毒力。该假设将通过实现以下特定目的来检验：1）确定调节RYFA1和RYFA2产生的铁和温度响应因子； 2）通过识别每个调节靶标的ryfa1和ryfa2的功能； 3）确定ryfa1和ryfa2的影响，单独和结合，对s. s. dysenteriae毒力。拟议的重复SRNA，RYFA1和RYFA2的系统表征将有助于回答志贺氏菌发病机理和细菌SRNA领域的基本问题，这将有助于实现长期目标的治疗治疗方法来治疗Shigellisosis。拟议的研究提出了一种创新的假设，即具有95％序列身份和相同预测结构的两个SRNA分子具有非冗余功能。该假设将使用标准，友好，细菌遗传学和创新高科技测定法的平衡方法进行检验。学生参与拟议的研究的每一步，构成了创新培训计划的基础，该计划将为学生提供细菌发病机理和基于RNA的调节领域的实践经验。最终的技能和经验组合将使学生充分地定位，以促进致病细菌，共生细菌和真核系统的核糖调节领域的迅速发展。