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: 10364241
• 负责人: John David Spencer
• 金额: $ 55.36万
• 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/10364241
• 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; Epithelial; 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; Pharmaceutical Preparations; Pharmacology; Prediabetes syndrome; Predisposition; Prevention strategy; Production; Proteins; Publishing; Receptor Activation; Receptor Signaling; Regenerative response; Research; Role; Signal Transduction; Site; Specific qualifier value; Therapeutic; To specify; Translations; Urinary tract; Urinary tract infection; Uropathogenic E. coli; Urothelial Cell; Urothelium; Work; antimicrobial; antimicrobial peptide; collecting tubule structure; defense response; experimental study; fighting; improved; infection management; infection risk; insight; insulin sensitivity; insulin sensitizing drugs; insulin signaling; microbial; mouse model; 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，包括感染风险增加。患糖尿病的人， 最常见的感染部位是尿路。在糖尿病患者中，尿路感染(UTI) 更常见，结果更糟糕。糖尿病患者易患尿路感染的机制不是 已定义。更好地理解保护尿路免受微生物侵袭的宿主防御机制 开发新的尿路感染预防和治疗策略需要侮辱。此应用程序的目标是识别 胰岛素信号如何调节膀胱的先天免疫防御。我们已发布和支持的数据 证明膀胱尿路上皮防御系统受胰岛素介导的靶点调节，包括过氧化物酶 增殖物激活受体γ(PPARγ)、胰岛素受体信号转导和组蛋白脱乙酰酶蛋白。 具体地说，我们的数据表明，PPARγ激活和组蛋白脱乙酰酶抑制增强了胰岛素信号转导， 加强尿路上皮屏障，增强天然免疫力，包括产生抗菌肽 和尿路上皮屏障。相反，抑制尿路上皮胰岛素受体的表达会增加尿路感染的易感性。 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 先天免疫反应和调节UTI宿主防御。在这些发现的基础上，我们提出了 综合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是否会触发胰岛素信号来增强免疫防御和减少尿路感染 敏感度。Aim 2将询问胰岛素受体信号对膀胱免疫防御的影响 尿路上皮对尿路感染的反应和修复。目标3将确定组蛋白脱乙酰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找出为什么糖尿病患者 增加了尿路感染的风险，并改善了他们的护理。通过评估胰岛素信号在宿主防御中的作用，我们的 预期结果可能会对人类健康产生深远影响，因为它们可能会形成胰岛素信号靶标。 作为新的尿路感染疗法。