PATHOGENIC MECHANISMS IN UTI

尿路感染的致病机制

基本信息

批准号：
7498757
负责人：
WALTER E STAMM
金额：
$ 20.06万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-02-24 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7498757
关键词：
Accounting Acute Acute Cystitis Address Adherence Affect Applications Grants Area Authorization documentation Bacterial Adhesins Bacterial Genes Bacteriuria Binding Biological Assay Bladder Candidate Disease Gene Caveolae Cell membrane Cell surface Cells Cystitis DNA DNA Microarray Chip DNA Microarray format Data Development Disclosure Doctor of Philosophy Ecology Epidemiology Epithelial Epithelial Cells Epithelium Escherichia coli Evolution Face Fred Hutchinson Cancer Research Center Funding Gene Expression Genes Genome Genomic Hybridizations Genomics Globosides Glycosphingolipids Health Health Care Costs Human Resources IL6 gene IL8 gene IL8RB gene Incidence Infection Inflammation Institutes Instruction Interdisciplinary Study Interferons Invaded Kidney Laboratories Lactobacillus Last Name Lead Mass Spectrum Analysis Methods Molecular Mutation Names National Institute of Diabetes and Digestive and Kidney Diseases Numbers Other Resources Pathogenesis Phagocytosis Phase II Clinical Trials Pilum Point Mutation Polymerase Chain Reaction Predisposition Prevalence Prevention Prevention approach Principal Investigator Probiotics Program Research Project Grants Progress Reports Pseudomonas Pseudomonas aeruginosa Public Health Pyelonephritis Rate Recurrence Research Research Personnel Research Project Grants Role Role playing therapy Sampling Scanning Soman Systems Biology TLR2 gene TLR4 gene TLR6 gene Techniques Technology Time Tissues Toll-like receptors Universities Urinary tract Urinary tract infection Uropathogen Vagina Washington Woman antimicrobial base chemokine receptor cohort density double-blind placebo controlled trial follow-up improved insight interest medical schools membrane assembly microbial microbial host microbicide new technology novel novel strategies programs receptor response uptake

项目摘要

An estimated 150 million UTIs occur annually on a global basis, accounting for direct health care costs exceeding 6 billion dollars and making UTIs a very significant public health burden. This program project proposes studies that will improve our understanding of the epidemiology, microbial ecology, molecular pathogenesis and prevention of UTIs. The objectives of the project will be met through the development of a multidisciplinary research team that will collaborate to carry out four interrelated projects. Project 1 will undertake a double-blind placebo-controlled trial to determine whether a Lactobacillus crispatis vaginal probiotic will reduce the incidence of recurrent UTIs in women. The trial will also study adherence of the probiotic strain to vaginal epithelial cells from the subjects and will thus provide insight into the host and microbial mechanisms involved. Project 2 will address the hypothesis that cell surface glycosphingolipids in the bladder and vaginal epithelium are structurally organized into pleotrophic plasma membrane assemblies called caveolae and that caveolae participate in the initial epithelial response to attachment and uptake of uropathogenic e. coil Project 3 will employ two novel technologies that were developed during the previous funding period, namely high density microarrays and whole genome mutation scanning to characterize on a genomic level the molecular adaptation that uropathogenic E. coil strains undergo in the course of recurrent UTIs and in shifting from an asymptomatic to symptomatic infection. The project will also define how such adaptive evolution affects the ability of uropathogens to bind and invade epithelial cells, induce inflammation and resist phagocytosis. In Project 4, the association of host susceptibility to recurrent cystitis or pyelonephritis with known or novel mutations in specifically selected candidate host genes will be examined. The candidate genes to be studied are toll-like receptors (TLR2, TLR4, and TLR6), chemokine receptors (CXCRI and CXCR2), and interferon y receptors (IFN-yR1 and IFN-yR2). A laboratory core will provide microbiological studies, primary bladder and vaginal epithelial cells, characterization of urovirulence genes,bacterial adherence assays and other resources to the projects. An Administrative/Biostatistical Core will coordinate the overall project and provide biostatistical expertise to all investigators. The proposed studies will result in an improved understanding of pathogenetic mechanisms in UTIs and will result in new approaches to prevention of UTIs.

估计每年在全球范围内发生1.5亿UTI，占直接医疗保健费用超过60亿美元，并使UTIS成为非常重大的公共健康负担。这个程序项目提出的研究将提高我们对流行病学，微生物生态学，分子发病机理和预防UTI的理解。该项目的目标将通过开发多学科研究团队将合作开展四个相互关联的项目。项目1将进行双盲安慰剂对照试验，以确定是否阴道益生菌将减少女性反复发作的尿路感染率。该试验还将研究益生菌菌株对受试者的阴道上皮细胞的依从性，从而提供对宿主的见解和涉及的微生物机制。项目2将解决以下假设：膀胱和阴道上皮的细胞表面糖磷脂在结构上组织成全质营养性质膜组件称为小窝，而小窝参与了对尿道病E的附着和摄取的最初上皮反应。线圈项目3将采用两种新型技术，这些技术是在上一次开发的资金时期，即高密度微阵列和整个基因组突变扫描，以在基因组水平上表征分子适应性的分子适应性，即在复发过程中进行尿道病的E.线圈菌株发生 UTI以及从无症状到有症状感染的转变。该项目还将定义这种适应性进化如何影响尿道病的能力结合和侵袭上皮细胞，诱发炎症并抵抗吞噬作用。在项目4中，将检查宿主对复发性膀胱炎或肾盂肾炎的易感性与已知或新型突变的特定候选宿主基因的关联。要研究的候选基因是Toll样受体（TLR2，TLR4和TLR6），趋化因子受体（CXCRI和CXCR2）以及干扰素Y受体（IFN-yr1和IFN-yr1和IFN-yr2）。实验室核心将提供微生物研究，原发性膀胱和阴道上皮细胞，尿路毒害基因的表征，细菌依从性测定和其他资源。行政/生物统计核心将协调整个项目，并为所有研究人员提供生物统计学专业知识。拟议的研究将导致对UTI的致病机制的了解，并将导致预防UTI的新方法。

项目成果

期刊论文数量（50）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A new candidate vaccine for Escherichia coli pyelonephritis.

一种新的大肠杆菌肾盂肾炎候选疫苗。

DOI：
10.1097/01.ju.0000118141.06761.14
发表时间：
2004
期刊：
The Journal of urology
影响因子：
0
作者：
Stapleton,Ann
通讯作者：
Stapleton,Ann

Variation in frequency of the virulence-factor gene in Escherichia coli clones colonizing the stools and urinary tracts of healthy prepubertal girls.

定植于健康青春期前女孩的粪便和尿道的大肠杆菌克隆毒力因子基因频率的变化。

DOI：
10.1086/377643
发表时间：
2003
期刊：
The Journal of infectious diseases
影响因子：
0
作者：
Schlager,TheresaA;Whittam,ThomasS;Hendley,JO;Bhang,JuneL;Wobbe,CherylL;Stapleton,A
通讯作者：
Stapleton,A

Theodore E. Woodward Award: host-pathogen interactions in community-acquired urinary tract infections.

西奥多·E·伍德沃德奖：社区获得性尿路感染中宿主与病原体的相互作用。

DOI：
发表时间：
2006
期刊：
Transactions of the American Clinical and Climatological Association
影响因子：
0
作者：
Stamm,WalterE
通讯作者：
Stamm,WalterE

Toll-like receptor polymorphisms and susceptibility to urinary tract infections in adult women.

DOI：
10.1371/journal.pone.0005990
发表时间：
2009-06-22
期刊：
PloS one
影响因子：
3.7
作者：
Hawn TR;Scholes D;Li SS;Wang H;Yang Y;Roberts PL;Stapleton AE;Janer M;Aderem A;Stamm WE;Zhao LP;Hooton TM
通讯作者：
Hooton TM

ABO and P1 blood group antigen expression and stx genotype and outcome of childhood Escherichia coli O157:H7 infections.

儿童大肠杆菌 O157:H7 感染的 ABO 和 P1 血型抗原表达以及 stx 基因型和结果。

DOI：
10.1086/338480
发表时间：
2002
期刊：
The Journal of infectious diseases
影响因子：
0
作者：
Jelacic,Srdjan;Wobbe,CherylL;Boster,DanielR;Ciol,MarciaA;Watkins,SandraL;Tarr,PhillipI;Stapleton,AnnE
通讯作者：
Stapleton,AnnE