Insulin Signaling Activates Urothelial Defenses to Reduce Urinary Tract Infection Susceptibility

胰岛素信号激活尿路上皮防御，降低尿路感染易感性

• 批准号: 10673963
• 负责人: John David Spencer
• 金额: $ 51.05万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673963
• 关键词: Affect; Agonist; Anatomy; Anti-Bacterial Agents; Bacteremia; Bladder; Bladder Urothelium; Caring; Cells; Cessation of life; Clinic; Coupled; Data; Defense Mechanisms; Diabetes Mellitus; Disease; Epithelium; Escherichia coli Infections; Goals; Health; Histone Deacetylase; Histone Deacetylase Inhibitor; Host Defense; Host Defense Mechanism; Human; Hyperglycemia; Immune; Immune response; Impairment; Infection; Infection prevention; Innate Immune Response; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Kidney; Knowledge; Laboratories; Lower urinary tract; Mediating; Molecular; Mus; Natural Immunity; Non-Insulin-Dependent Diabetes Mellitus; Outcome; PI3K/AKT; PPAR gamma; Persons; Pharmaceutical Preparations; Prediabetes syndrome; Predisposition; Prevention strategy; Production; Proteins; Publishing; Receptor Activation; Receptor Signaling; Regenerative response; Research; Role; Signal Transduction; Site; Specific qualifier value; Therapeutic; Translations; Urinary tract; Urinary tract infection; Uropathogenic E. coli; Urothelial Cell; Urothelium; Work; antimicrobial; antimicrobial peptide; collecting tubule structure; experimental study; fighting; improved; infection management; infection risk; insight; insulin sensitivity; insulin signaling; microbial; mouse model; pharmacologic; prevent; receptor expression; repaired; response; response to injury; treatment strategy

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.

项目摘要/摘要： 糖尿病与许多并发症有关，包括增加感染风险。糖尿病，一个 最常见的感染部位是尿路。在糖尿病患者中，尿路感染（UTI）为 更常见，结果更糟。使糖尿病患者易于使用UTI的机制不是 定义。对保护尿路免受微生物的宿主防御机制的更大欣赏 需要侮辱来制定新的预防UTI和治疗策略。此应用程序的目标是确定 胰岛素信号如何调节膀胱中的先天免疫防御能力。我们已发布和支持数据 证明膀胱尿路上皮防御受胰岛素介导的靶标的调节，包括过氧 增殖物激活的受体-γ（PPARγ），胰岛素受体信号传导和组蛋白脱乙酰基酶蛋白。 具体而言，我们的数据表明PPARγ激活和组蛋白脱乙酰基酶抑制增强胰岛素信号传导， 增强尿路上皮屏障并增强先天免疫力，包括抗菌胡椒的产生 和尿路上皮障碍。相反，沉默的尿路上皮胰岛素受体表达增加了UTI的敏感性。 这些数据支持我们的中心假设，即胰岛素和胰岛素受体信号在激活中具有关键作用 先天免疫反应和控制UTI宿主防御。扩大这些发现，我们提出了一个 胰岛素调节膀胱尿路上皮防御机制的能力的全面分析。目标1意志 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 还将调查激活PPARγ是否触发胰岛素信号传导以增强免疫防御并减少UTI 敏感性。 AIM 2将询问胰岛素受体信号传导对膀胱免疫防御的影响 以及尿路上皮的反应和对UTI的修复。 AIM 3将定义组蛋白脱乙酰基蛋白对胰岛素的影响 信号和膀胱的免疫防御能力。我们的长期研究目标是确定为什么患有糖尿病的人。 增加了UTI风险并改善他们的护理。通过评估胰岛素信号在宿主防御中的作用，我们 预期的结果可能会对人类健康产生深远的影响，因为它们可能会发展出胰岛素信号目标 作为新的UTI疗法。