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.

项目总结/文摘: