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.

由尿路致病性大肠杆菌 (UPEC) 引起的尿路感染 (UTI) 导致 800 万人门诊就诊 在美国，每年的就诊次数（主要是女性）和超过 10 亿美元的医疗保健费用 复发性尿路感染 (rUTI) 是 一个重大问题：>25% 患有急性尿路感染的女性会在 6 个月内出现重复性尿路感染。到 为了解决这个问题，项目 2 正在招募一组患有急性膀胱炎的女性，但最近没有发现 尿路感染史。从这些患者的尿液中分离出的细菌将在我们的小鼠模型中进行表征 项目 1. 我们详细介绍了小鼠体内 UPEC 侵入表层伞细胞的致病循环 排列在膀胱内并快速复制形成密集的生物膜状细胞内细菌 社区（IBC）。 IBC 内的细菌受到保护，免受宿主先天免疫防御和许多 抗生素，从而使一种细菌能够在数小时内克隆复制到 10,000 种或更多细菌 感染。 IBC 最终分散，细菌从细胞中流出并继续重复 IBC 循环 在另一个上皮细胞内或继续形成静态细胞内储库（QIR）。 QIR 可以持续存在 持续数月，然后播种 rUTI。我们将确定IBC和QIR的形成是否是通用的 UPEC 的特性以及这些循环的显着特征在引起不同的细菌之间是否存在差异 临床尿路感染综合征（无症状菌尿、急性感染或反复感染） 不同的宿主遗传背景。我们已完成膀胱炎菌株UTI89的基因组序列 项目 3 将使用它和附加序列信息来通过计算搜索候选者 发病机制和复发的遗传决定因素。这些候选基因将在我们的分析中进行分析 小鼠模型，部分通过使用先进的成像方法、激光研究突变的影响 捕获显微解剖、功能基因组学和 gfp 融合。主机响应的特点是 免疫组织学、流式细胞术和细胞学。质谱分析将用于分析定性和 宿主和病原体因素的定量变化，以识别那些具有病理生理学和病理学特征的因素 预后意义。 SCOR 中三个项目的综合专业知识将允许协调一致 努力了解女性尿路感染的流行病学和基本致病机制，使我们能够 开始解决尿路感染管理中的临床问题。