权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

TARGETING THE E COLI CHAPERONE SURA IN RECURRENT UTI

针对复发性尿路感染中的大肠杆菌伴侣 SURA

基本信息

批准号：
8168719
负责人：
DAVID ALAN HUNSTAD
金额：
$ 0.97万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-10 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8168719
关键词：
Adhesives Affect Anti-Infective Agents Antibiotic Therapy Antibiotics Biochemical Biological Assay Bladder Bladder Tissue Cell Line Cells Child Chronic Chronic Kidney Failure Collection Communicable Diseases Communities Computer Retrieval of Information on Scientific Projects Database Cystitis Data Development Epithelial Cells Escherichia coli Funding Grant Growth Immune Infection Inflammatory Institution Invaded Knowledge Lead Medical Membrane Modeling Molecular Chaperones Morbidity - disease rate Mus Mutagenesis Oral Outpatients Pain Pathogenesis Pathway interactions Patients Phenotype Pilum Plague Population Production Proteins Recurrence Regimen Research Research Personnel Resources Seeds Source United States United States National Institutes of Health Urinary tract Urinary tract infection Uropathogenic E. coli Virulence Visit Woman Work bacterial resistance cost cytokine extracellular gastrointestinal kidney infection novel pathogen periplasm renal scarring

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Urinary tract infections (UTIs), most commonly caused by uropathogenic Escherichia coli (UPEC), are associated with substantial morbidity and medical cost. Affected women and children are often plagued with recurrences, and repeated infections of the kidney can lead to renal scarring and chronic kidney disease. Recent work in the murine cystitis model has unveiled new paradigms regarding the pathogenesis of UTI. Long thought to be a strictly extracellular pathogen, UPEC has been shown to invade the epithelial cells lining the bladder and to establish large collections, termed intracellular bacterial communities (IBCs), within these cells. UPEC forms a quiescent reservoir within bladder tissue that resists oral antibiotic therapy and is invisible to host immune defenses, a phenotype that may depend on its unique ability to downregulate host inflammatory cytokine production. This bacterial reservoir can then serve as a seed for recurrent infection, a finding that challenges current dogma that recurrent UTI represents re-inoculation of the urinary tract from a gastrointestinal E. coli population. Current antibiotic regimens are challenged by the development of bacterial resistance and do not eradicate the chronic reservoir. Our recent data demonstrate that a conserved periplasmic chaperone called SurA is critical for the production of adhesive type 1 pili, for the UPEC anti-cytokine phenotype, and for intracellular growth of UPEC during IBC maturation. Disruption of SurA function in UPEC also abolishes formation of the quiescent bacterial reservoir. We will employ tagged SurA proteins in a set of biochemical assays to determine the spectrum of outer membrane substrates of this important conserved chaperone in UPEC. Domain complementation and mutagenesis will be performed to delineate the structural features of, and residues within, SurA that are critical for its support of virulence in UPEC. This knowledge will lead to the development of novel anti-infective compounds that target SurA function and interrupt the IBC pathway and the cycle of recurrent UTI. Relevance: Urinary tract infections represent the second most common infectious disease in the United States, with an annual burden of > 7 million outpatient visits and $1 billion in medical cost. Many patients suffer from recurrences that are not only disruptive and painful but can also lead to chronic kidney disease, and current therapies for these patients are insufficient. This proposal identifies a new target for interrupting the cycle of recurrent urinary tract infection.

这个子项目是众多研究子项目之一