ORWH: SCOR on Sex and Gender Factors Affecting Women's Health

ORWH：SCOR 关于影响女性健康的性和性别因素

• 批准号: 8329466
• 负责人: SCOTT J. HULTGREN
• 金额: $ 40.43万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8329466
• 关键词: AKR/J Mouse; Acute; Acute Cystitis; Address; Affect; Antibiotic Therapy; Antibiotics; Back; Bacteria; Bacterial Antibiotic Resistance; Bacterial Genes; Bacteriuria; Basic Science; Biological; Biological Assay; Biological Markers; Bladder; Bladder Tissue; C3H/HeN Mouse; Candidate Disease Gene; Carrier Proteins; Cell Line; Cells; Chromosomes; Chronic; Chronic Cystitis; Clinical; Clinical Sciences; Clinical Treatment; Collaborations; Communities; Confocal Microscopy; Cystitis; Cytology; Data; Defensins; Diagnosis; Diagnostic Procedure; Diffuse; Disease; Disease Outcome; Enrollment; Enzyme-Linked Immunosorbent Assay; Epidemiology; Epithelial Cells; Escherichia coli Infections; Essential Genes; Flow Cytometry; Funding; Future; Gender; Gene Deletion; Gene Targeting; Genes; Genetic; Genetic Determinism; Genetic Techniques; Genomics; Goals; Health Care Costs; Host Defense; Hour; Human; Immune; Immune response; Immunohistochemistry; In Vitro; Inbred Mouse; Inbreeding; Incidence; Infection; Intervention Studies; Invaded; Investigation; Iron; Kinetics; Knowledge; Lead; Life; Mass Spectrum Analysis; Mediating; Methods; Microbial Biofilms; Microscopic; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Mouse Strains; Mus; Mutation; Natural regeneration; Outcome; Outpatients; Pathogenesis; Pathogenicity; Pathogenicity Island; Patients; Phenotype; Physicians; Pilum; Plasmids; Prevention; Production; Prognostic Factor; Property; Proteins; Pyelonephritis; Pyelonephritis strains; Recording of previous events; Recurrence; Regimen; Reporting; Research; Research Personnel; Resolution; Role; Seeds; Severity of illness; Siderophores; Signal Transduction; Site; Surface; Syndrome; System; Testing; Therapeutic; Time; Urethra; Urinary tract; Urinary tract infection; Urine; Uropathogen; Uropathogenic E. coli; Variant; Virulence; Virulence Factors; Visit; Woman; Women' s Health; bacterial genetics; base; clinical Diagnosis; clinically relevant; cohort; cost; cystitis strains; cytokine; defense response; experience; extracellular; functional genomics; gene function; genome sequencing; imaging modality; in vivo; insight; laser capture microdissection; mouse model; novel strategies; novel therapeutics; pathogen; prevent; prognostic; programs; promoter; protein transport; prototype; research study; response; sex; synthetic polymer Bioplex; synthetic protein; tissue culture

Urinary tract infections (UTI) caused by uropathogenic Escherichia coli (UPEC) result in 8 million outpatient visits (mostly by women) and over $1 billion in health care costs annually in the U.S. Recurrent UTI (rUTI) is a significant problem: >25% of women who suffer from an acute UTI experience a rUTI within 6 months. To address this problem, Project 2 is enrolling a cohort of women presenting with acute cystitis but no recent history of UTI. Bacterial isolates from the urine of these patients will be characterized in our mouse model in Project 1. We have detailed a pathogenic cycle within mice in which UPEC invade superficial umbrella cells that line the bladder and rapidly replicate to form a densely packed, biofilm-like intracellular bacterial community (IBC). Bacteria within an IBC are protected from both host innate immune defenses and many antibiotics, thus allowing one bacterium to clonally replicate to 10,000 or more bacteria within hours after infection. IBCs eventually disperse, with bacteria fluxing out of the cells and going on to repeat the IBC cycle within another epithelial cell or going on to form a quiescent intracellular reservoir (QIR). QIRs can persist for months and then later seed a rUTI. We will determine whether IBC and QIR formation is a general property of UPEC and whether prominent features of these cycles differ between bacteria causing different clinical UTI syndromes (asymptomatic bacteriuria, acute infection, or recurrent infection) and between different host genetic backgrounds. We have completed the genome sequence of cystitis strain UTI89 in Project 3 and will use this with additional sequence information to computationally search for candidate genetic determinants of pathogenesis and recurrence. These candidate genes will be analyzed in our murine model, in part by investigating the effects of mutations using advanced imaging methods, laser capture microdissection, functional genomics, and gfp fusions. Host responses will be characterized by immunohistology, flow cytometry, and cytology. Mass spectrometry will be used to profile qualitative and quantitative changes in both host and pathogen factors to identify those with pathophysiologic and prognostic significance. The combined expertise of the three projects in this SCOR will allow a coordinated effort to understand the epidemiology and basic pathogenic mechanisms of UTIs in women, allowing us to begin addressing clinical questions in the management of UTI.

尿路感染（UTI）是由尿道病大肠杆菌（UPEC）引起的，导致800万门诊病人 在美国复发性UTI（RUTI）每年访问（主要由妇女）和超过10亿美元的医疗保健费用是 一个重大的问题：> 25％的女性在6个月内遭受急性UTI经历RUTI。到 解决这个问题，项目2正在招募一群患有急性膀胱炎的女性，但最近没有 UTI的历史。这些患者尿液中的细菌分离株将在我们的小鼠模型中表征 项目1。我们详细介绍了小鼠中的致病周期，其中UPEC入侵了浅表伞细胞 那条线膀胱并快速复制以形成一个堆积的，类似生物膜的细胞内细菌 社区（IBC）。 IBC内的细菌均受到宿主先天免疫防御和许多的保护 抗生素，因此允许一种细菌在后数小时内将一个细菌复制至10,000个或更多细菌 感染。 IBC最终分散了，细菌磁通从细胞中流出并继续重复IBC循环 在另一个上皮细胞内或形成静止的细胞内储层（QIR）。 QIR可以持续存在 几个月，然后播种ruti。我们将确定IBC和QIR组是否是一般 UPEC的属性以及这些周期的突出特征是否不同，导致不同的细菌 临床UTI综合征（无症状的细菌，急性感染或复发感染）以及之间 不同的宿主遗传背景。我们已经完成了膀胱炎菌株UTI89的基因组序列 项目3，并将将其与其他序列信息一起用于计算搜索候选人 发病机理和复发的遗传决定因素。这些候选基因将在我们的 鼠模型，部分通过使用高级成像方法研究突变的效果，激光 捕获微分解，功能基因组学和GFP融合。主机回答将以特征 免疫组织学，流式细胞仪和细胞学。质谱法将用于概述定性和 宿主和病原体因素的定量变化，以鉴定患有病理生理和 预后意义。该SCOR中三个项目的总专业知识将允许协调 努力了解女性UTI的流行病学和基本致病机制，使我们能够 开始在UTI管理中解决临床问题。