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

项目总结/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UTI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单纯基于 抗生素治疗因此，需要用于UTI治疗和预防的替代方法。的衬里 泌尿道或尿道，在检测和清除入侵细菌中起重要作用， 包括产生细胞因子和抗菌肽（AMP）。这些先天防御的内在品质 在泌尿系统内可能被利用治疗来预防和治疗UTI。基本知识 然而，我们对这些不同因素如何限制UTI易感性的理解存在差距。 本研究项目的目的是确定膀胱尿路上皮保护膀胱癌的机制。 泌尿道感染致病性细菌。这一提议验证了细胞因子 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 转导子和转录激活子3（Stat 3）转录因子和AMP产生。预期 这项研究的结果是建立IL-6/Stat 3/AMP信号转导级联的贡献， 尿道炎的宿主防御特性目的1将研究IL-6如何直接限制尿路上皮细胞 对UTI敏感。目的2将建立尿路上皮Stat 3在UTI中的作用。目标3将探讨 抗菌肽预防尿路感染总之，这些目的旨在暗示IL-6/Stat 3/AMP途径是关键驱动因素， 尿路上皮对UTI的易感性，并因此作为UTI治疗的潜在目标。完成这个奖项 将联合收割机结合结构化的职业发展活动和指导研究项目，以实现过渡 从一个初级调查员到一个独立资助的外科医生科学家。

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.