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

项目摘要/摘要 尿路感染是患者发病率的常见来源，可导致永久性肾脏损害。从历史上看， 抗生素一直是尿路感染治疗的标准，并经常用于预防。然而，出现了 多药耐药尿路病原体的数量限制了仅基于 抗生素治疗。因此，治疗和预防尿路感染的替代方法是必要的。的衬里 尿路或尿路上皮在检测和清除入侵细菌方面起着至关重要的作用， 包括生产细胞因子和抗菌肽(AMP)。这些与生俱来的防御品质 尿路上皮内可用于治疗以预防和治疗尿路感染。基础知识 然而，在我们对这些不同因素如何影响尿路感染易感性的理解上存在差距。 本研究项目的目的是明确膀胱尿路上皮保护膀胱的机制。 尿路由入侵的泌尿病原菌引起。这一提议检验了细胞因子的假设 白介素6(IL-6)通过激活信号促进致尿路病原性大肠杆菌的清除 转录转导和激活因子3(STAT3)转录因子和AMP的产生。预期中的 本研究的结果是建立了IL-6/STAT3/AMP信号转导通路在 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 对尿路感染的敏感性。目的2将确定尿路上皮STAT3在尿路感染中的作用。目标3将探讨其影响 AMPS在预防UTI中的作用。总而言之，这些目标看起来意味着IL-6/STAT3/AMP途径是一个关键驱动因素 尿路上皮对尿路感染的敏感性增加，因此成为尿路感染治疗的潜在靶点。本奖项的完成 将结合有组织的职业发展活动和有指导的研究计划，以实现过渡 从初级调查员到独立资助的外科医生兼科学家。

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.