Deciphering the source and consequences of Nur77 expression during E. coli rUTI in mice

破译小鼠大肠杆菌 rUTI 期间 Nur77 表达的来源和后果

基本信息

  • 批准号:
    10431538
  • 负责人:
  • 金额:
    $ 11.81万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-04-01 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT Recurrent urinary tract infection (rUTI) is a costly clinical problem that affects millions of women worldwide and contributes to the global rise in antibiotic resistance. Multiple lines of evidence indicate that bacteria in the vagina can affect susceptibility to UTI. For example, women with the vaginal dysbiosis called bacterial vaginosis (BV) are at increased risk of UTI. Several vaginal bacteria—including the BV-associated species Gardnerella vaginalis (G.v.)—have been isolated from urine collected directly from the bladder by needle aspiration or transurethral catheterization. Although culture conditions are not often poised to detect it, the presence of G.v. in urine is also epidemiologically linked with rUTI. We have developed new mouse models to define the impact of vaginal bacteria on UTI from a new perspective—testing the idea that transient bladder exposures to vaginal bacteria such as G.v. influence the pathogenesis of Escherichia coli (E.c.), the leading cause of UTI. We previously demonstrated that G.v. triggers apoptosis and exfoliation of the bladder epithelium in mice. When mice harbored latent intracellular bladder reservoirs of E.c. from a prior experimental infection, G.v. triggered emergence of E.c. and rUTI at a rate 4-fold higher than mice exposed to vehicle alone. These data indicate that bladder exposures to G.v. could represent a trigger of rUTI in women. To understand at the cellular and molecular level how G.v. triggers exfoliation and rUTI, we have examined the transcriptional response to G.v. in the bladder using bulk RNA sequencing. This analysis revealed that G.v. induced the expression of the orphan nuclear receptor Nur77 (also called Nr4a1). Nur77 is well-recognized for its role in apoptosis and in inflammatory responses in diseases in other tissues, but its role in the urinary tract is largely unstudied. Our preliminary data using Nur77-/- mice indicate that Nur77 is required for G.v. to trigger E.c. rUTI in our mouse model. In this focused R03, we seek to answer two fundamental questions regarding the contribution of Nur77 to G.v.-induced E.c. rUTI: Which cell types in the bladder express Nur77 following G.v. exposure? (Aim 1), and Which host responses to G.v. exposure—exfoliation or inflammatory cytokine production—are mediated by Nur77? (Aim 2). Our proposed experiments build upon our preliminary data and leverage available Nur77 knockout and reporter mice and our experience in detailing bladder responses to microbial exposures. Successful completion of these studies will provide important mechanistic insights into how G.v. triggers E.c. rUTI and will generate key data on which to build a future R01 proposal.
摘要

项目成果

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Nicole Marie Gilbert其他文献

Nicole Marie Gilbert的其他文献

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{{ truncateString('Nicole Marie Gilbert', 18)}}的其他基金

A co-infection model for papillomavirus associated infections and cancers
乳头瘤病毒相关感染和癌症的共感染模型
  • 批准号:
    10667710
  • 财政年份:
    2023
  • 资助金额:
    $ 11.81万
  • 项目类别:
Deciphering the source and consequences of Nur77 expression during E. coli rUTI in mice
破译小鼠大肠杆菌 rUTI 期间 Nur77 表达的来源和后果
  • 批准号:
    10593109
  • 财政年份:
    2022
  • 资助金额:
    $ 11.81万
  • 项目类别:
Role of Gardnerella vaginalis in the Urinary Tract
阴道加德纳菌在尿道中的作用
  • 批准号:
    9912142
  • 财政年份:
    2017
  • 资助金额:
    $ 11.81万
  • 项目类别:

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