Urothelial IL-6 Signaling in the Host Defense Against Urinary Tract Infections

尿路上皮 IL-6 信号在宿主防御尿路感染中的作用

基本信息

批准号：
10615681
负责人：
Christina B Ching
金额：
$ 16.2万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10615681
关键词：
Accounting Affect Antibiotic Resistance Antibiotic Therapy Antibiotics Award Bacteria Bacterial Antibiotic Resistance Bacterial Infections Bladder Urothelium Child Communities Data Detection Development Emergency department visit Escherichia coli Infections Funding Gene Expression Healthcare Host Defense IL6ST gene Immune signaling In Vitro Infection Innate Immune Response Interleukin 6 Receptor Interleukin-6 Invaded Knowledge Measures Mentors Methods Modernization Morbidity - disease rate Multi-Drug Resistance Natural Immunity Outcome Outcomes Research Pathogenesis Pathway interactions Patients Peptide Signal Sequences Phenotype Population Predisposition Prevention Production Property Public Health Publishing Receptor Signaling Recurrence Renal function Research Research Personnel Research Project Grants Resources Role Scientist Severities Signal Pathway Signal Transduction Source Stat3 protein Structure Surgeon Testing Therapeutic Transcription Factor 3 Transgenic Mice United States Urinary tract Urinary tract infection Urine Uropathogen Uropathogenic E. coli Urothelial Cell Urothelium Virulence Work antimicrobial antimicrobial peptide career development chronic infection clinical care clinically significant cytokine in vivo infection risk overexpression pathogen prevent programs prophylactic renal damage renal scarring therapeutic target transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT UTIs are a common source of patient morbidity that can result in permanent renal damage. Historically, antibiotics have been the standard in UTI treatment and routinely used for prevention. However, the emergence of multidrug resistant uropathogens limits the long-term viability of antimicrobial strategies based solely on antibiotic therapy. As a result, alternative methods for UTI treatment and prevention are needed. The lining of the urinary tract, or urothelium, serves essential roles in the detection and elimination of invading bacteria, including production of cytokines and antimicrobial peptides (AMPs). These intrinsic qualities of innate defense within the urothelium might be harnessed therapeutically to prevent and treat UTI. A fundamental knowledge gap exists, however, in our understanding of how these different factors contribute to limiting UTI susceptibility. The objective of this research project is to define the mechanisms by which the bladder urothelium defends the urinary tract from invading uropathogenic bacteria. This proposal tests the hypothesis that the cytokine interleukin-6 (IL-6) promotes clearance of uropathogenic Escherichia coli through activation of the Signal transducer and activator of transcription 3 (Stat3) transcription factor and AMP production. The anticipated outcome of this research is to establish the contributions of the IL-6/Stat3/AMP signal transduction cascade to the host defense properties of the urothelium. Aim 1 will investigate how IL-6 directly limits urothelial susceptibility to UTI. Aim 2 will establish the roles for urothelial Stat3 during UTI. Aim 3 will explore the impact of AMPs in preventing UTI. Together, these Aims look to implicate the IL-6/Stat3/AMP pathway as a key driver of urothelial susceptibility to UTI and thus as a potential target of UTI treatment. The completion of this award will combine structured career development activities and mentored research programs to enable the transition from a junior investigator to an independently funded surgeon-scientist.

项目概要/摘要尿路感染是患者发病的常见原因，可导致永久性肾损伤。从历史上看，抗生素已成为尿路感染治疗的标准，并常规用于预防。然而，出现多重耐药尿路病原体的存在限制了仅基于抗生素策略的长期可行性抗生素治疗。因此，需要治疗和预防尿路感染的替代方法。衬里泌尿道或尿路上皮在检测和消除入侵细菌方面发挥着重要作用，包括细胞因子和抗菌肽（AMP）的产生。这些先天防御的内在品质尿路上皮内的细菌可以通过治疗手段来预防和治疗尿路感染。一、基础知识然而，我们对这些不同因素如何限制尿路感染易感性的理解存在差距。该研究项目的目的是确定膀胱尿路上皮保护膀胱的机制。泌尿道免受泌尿道致病细菌的侵袭。该提议检验了细胞因子的假设白细胞介素 6 (IL-6) 通过激活信号促进尿路致病性大肠杆菌的清除转录转导子和转录激活子 3 (Stat3) 转录因子和 AMP 生成。预计的这项研究的成果是确定 IL-6/Stat3/AMP 信号转导级联对尿路上皮的宿主防御特性。目标 1 将研究 IL-6 如何直接限制尿路上皮对尿路感染的易感性。目标 2 将确定尿路上皮 Stat3 在 UTI 期间的作用。目标 3 将探讨影响 AMP 在预防 UTI 中的作用。这些目标共同表明 IL-6/Stat3/AMP 通路是关键驱动因素尿路上皮对尿路感染的易感性，因此可以作为尿路感染治疗的潜在目标。本次奖励完成情况将结合结构化的职业发展活动和指导研究计划以实现过渡从初级研究员到独立资助的外科医生科学家。