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Cellular and Molecular Basis of Sex Specificity in UTI Pathogenesis

UTI 发病机制中性别特异性的细胞和分子基础

基本信息

批准号：
10094726
负责人：
Ashlee Miriam Earl
金额：
$ 48.69万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10094726
关键词：
Acute Affect Anatomy Androgen Receptor Androgenization Androgens Antibiotics Automobile Driving Bacteria Bacterial Infections Bacterial RNA Biological Assay Bladder Bypass Catheters Cell Culture System Cell Nucleus Child Chronic Cystitis Chronic Kidney Failure Cicatrix Collaborations Communities Complement Factor B Complex Complication Data Epidemiology Epithelial Cells Escherichia coli Infections Exhibits Female Flow Cytometry Functional disorder Gastrointestinal tract structure Gene Expression Genetic Transcription Gonadal Steroid Hormones Health Healthcare Histology Hormonal Human Hybrids Hypertension Immune response In Vitro Inbred C3H Mice Incidence Infection Infective cystitis Kidney Knock-out Knockout Mice Laboratories Leukocytes Life Link Mediator of activation protein Methods Microscopy Modeling Molecular Morbidity - disease rate Mouse Strains Mus Myofibroblast Operative Surgical Procedures Outcome Pathogenesis Pathogenicity Pathway interactions Phenotype Polycystic Ovary Syndrome Population Pre-Clinical Model Predisposition Publishing Pyelonephritis Recurrence Resolution Risk SHH gene Severities Sex Differences Signal Pathway Signal Transduction Site Specific qualifier value Specificity Techniques Technology Testing Time To specify Transforming Growth Factors Tubular formation Universities Urethra Urinary tract Urinary tract infection Uropathogenic E. coli Vesico-Ureteral Reflux Virulence Virulence Factors Washington Woman Work activin A cell type conditional knockout epidemiologic data experimental study in vivo infection management infection risk innovation insight kidney fibrosis kidney infection macrophage male men minimally invasive mortality mutant novel pathogen patient population pre-clinical prevent programs recruit renal abscess renal epithelium renal scarring response sex transcriptome sequencing young adult

项目摘要

PROJECT SUMMARY In the proposed work, the Hunstad laboratory at Washington University will employ new models of urinary tract infection (UTI) in female, androgenized female, and male mice to determine molecular mechanisms by which host androgen exposure promotes uropathogenic Escherichia coli (UPEC) pyelonephritis as well as renal scarring, a common sequela of upper-tract UTI. Our recent findings indicate that the influence of sex, including androgen exposure, on these common bacterial infections is more complex than previously appreciated. Using newly developed and optimized models of UTI in mice, we recently demonstrated that androgen exposure is associated with increased risk for chronic cystitis and high-titer pyelonephritis, as well as formation of renal abscesses, in both male and female hosts. These findings correlate with epidemiologic data revealing higher morbidity and mortality in men who do suffer complicated UTI (compared with women), and higher incidence of UTI in women with a common hyperandrogenic condition (polycystic ovary syndrome). Moreover, we have demonstrated a separable effect of androgens on renal fibrosis (scarring), a common complication of pyelonephritis in children that can contribute to long-term sequelae such as hypertension and risk for chronic kidney disease. On the basis of these findings, we hypothesize that fundamental sex differences impact the host-pathogen interaction and cellular responses in pyelonephritis, thereby influencing pathogenicity, resolution, and subsequent renal scarring. To interrogate this hypothesis, and building on our published work, we will first comprehensively define host-sex-specific virulence requirements and sex influences on the host- pathogen interaction through single-nucleus RNA-seq, hybrid capture-enhanced bacterial RNA-seq, and insertion-site sequencing experiments on the infected kidney, in collaboration with MPI Dr. Earl and collaborator Dr. Humphreys. Candidate sex-discrepant host pathways and bacterial virulence factors will be confirmed and interrogated using germline and conditional knockout mice, bacterial mutants, and an array of bacterial pathogenesis studies. We will also define the molecular pathways underlying renal fibrosis following pyelonephritis, and how these pathways are modulated by sex and/or by androgen exposure at varying times before, during, and after UTI. In total, the proposed work will leverage new preclinical models and an array of conventional and cutting-edge experimental techniques. Our results will illuminate sex-specific host-pathogen interactions in the infected kidney and identify UPEC virulence factors important in sex-dependent outcomes of upper-tract UTI. In addition, our preclinical findings will also be translationally relevant to recurrent UTI and renal scarring in human patient populations.

项目总结