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

• 批准号: 10886954
• 负责人: Christina B Ching
• 金额: $ 7.99万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 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/10886954
• 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

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.

项目摘要/摘要 UTI是患者发病率的常见来源，可能导致永久性肾脏损害。从历史上看 抗生素一直是UTI治疗的标准，并通常用于预防。但是，出现 多药耐药性尿道病限制了抗菌策略的长期生存能力，仅基于 抗生素疗法。结果，需要用于UTI治疗和预防的替代方法。衬里 尿路或尿路上皮在检测和消除入侵细菌中起着重要作用 包括生产细胞因子和抗菌肽（AMPS）。这些天生防御的内在品质 在尿路上皮内可能会通过治疗来预防和治疗UTI。基本知识 但是，在我们对这些不同因素如何限制UTI易感性的理解中存在差距。 该研究项目的目的是定义膀胱尿铺捍卫的机制 尿路因入侵尿道病细菌。该建议检验了细胞因子的假设 白介素-6（IL-6）通过激活信号促进尿道病大肠杆菌的清除 转录3（STAT3）转录因子和AMP产生的换能器和激活因子。预期 这项研究的结果是建立IL-6/STAT3/AMP信号转导级联对 尿路上皮的宿主防御特性。 AIM 1将研究IL-6如何直接限制尿路上皮 对UTI的敏感性。 AIM 2将在UTI期间确定尿路上皮STAT3的作用。 AIM 3将探索影响 预防UTI的AMP。这些目标在一起，旨在将IL-6/STAT3/AMP途径视为关键驱动程序 尿路上皮易感性对UTI的敏感性，因此是UTI治疗的潜在靶标。该奖项的完成 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 从初级调查员到由独立资助的外科医生科学家。