Insulin Signaling Activates Urothelial Defenses to Reduce Urinary Tract Infection Susceptibility

项目概要/摘要： 糖尿病与许多并发症有关，包括感染风险增加。糖尿病，1 最常见的感染部位是泌尿道。尿路感染（UTI）是糖尿病的一种常见症状。 更常见，结果更糟。使糖尿病患者易患UTI的机制并非 定义了对保护尿路免受微生物侵害的宿主防御机制的更高认识 因此需要开发新UTI预防和治疗策略。此应用程序的目标是识别 胰岛素信号如何调节膀胱中的先天免疫防御。我们的已发表和支持数据 表明膀胱尿路上皮防御受胰岛素介导的靶点调节，包括过氧化物酶体 增殖物激活受体-γ（PPARγ）、胰岛素受体信号传导和组蛋白脱乙酰酶蛋白。 具体来说，我们的数据表明，PPARγ激活和组蛋白脱乙酰酶抑制增强胰岛素信号传导， 增强尿路上皮屏障，增强先天免疫，包括抗菌肽的产生 和尿路上皮屏障。相反，沉默尿路上皮胰岛素受体表达增加UTI易感性。 这些数据支持了我们的中心假设，即胰岛素和胰岛素受体信号在激活 先天免疫反应和调节UTI宿主防御。根据这些发现，我们提出了一个 全面分析胰岛素调节膀胱尿路上皮防御机制的能力。目标1将 确定进行性胰岛素抵抗和糖尿病对膀胱抗菌防御的影响。我们 我还将研究激活PPARγ是否触发胰岛素信号，以增强免疫防御和减少UTI 易感性目标2将询问胰岛素受体信号对膀胱免疫防御的影响 和尿路上皮反应以及对UTI的修复。目的3将明确组蛋白去乙酰化酶蛋白对胰岛素的影响 信号和膀胱的免疫防御。我们的长期研究目标是确定为什么糖尿病患者 增加了UTI的风险，并改善了他们的护理。通过评估胰岛素信号传导在宿主防御中的作用， 预期的结果可能对人类健康产生深远的影响，因为它们可能会产生胰岛素信号靶点 作为新的UTI疗法。

Project Summary/Abstract: Diabetes mellitus is associated with many complications, including increased infection risk. With diabetes, one of the most common sites of infection is the urinary tract. In people with diabetes, urinary tract infection (UTI) is more common and has worse outcomes. The mechanisms that predispose people with diabetes to UTI are not defined. A greater appreciation for the host defense mechanisms that protect the urinary tract from microbial insult is needed to develop new UTI prevention and treatment strategies. This application’s objective is to identify how insulin signaling regulates innate immune defenses in the bladder. Our published and supporting data demonstrate that bladder urothelial defenses are regulated by insulin-mediated targets, including peroxisome proliferator-activated receptor-γ (PPARγ), insulin receptor signaling, and histone deacetylase proteins. Specifically, our data suggest PPARγ activation and histone deacetylase inhibition enhance insulin signaling, strengthen the urothelial barrier, and enhance innate immunity, including the production of antimicrobial peptides and the urothelial barrier. In contrast, silencing urothelial insulin receptor expression increases UTI susceptibility. These data support our central hypothesis that insulin and insulin receptor signaling have key roles in activating innate immune responses and regulating UTI host defense. Expanding upon these findings, we propose a comprehensive analysis of insulin’s ability to regulate bladder urothelial defense mechanisms. Aim 1 will determine the effects of progressive insulin resistance and diabetes on the bladder’s antibacterial defenses. We will also investigate if activating PPARγ triggers insulin signaling to enhance immune defenses and reduce UTI susceptibility. Aim 2 will interrogate the impact of insulin receptor signaling on the bladder’s immune defenses and urothelial responses and repair to UTI. Aim 3 will define the effect of histone deacetylase proteins on insulin signaling and the bladder’s immune defenses. Our long-term research goal is to identify why people with diabetes have increased UTI risk and improve their care. By evaluating the role of insulin signaling in host defense, our expected outcomes may have profound influence on human health as they may develop insulin-signaling targets as new UTI therapeutics.