Linking Insulin Signaling to Antimicrobial Peptide Production and the Kidney's Antibacterial Defenses

将胰岛素信号转导与抗菌肽的产生和肾脏的抗菌防御联系起来

• 批准号: 9523793
• 负责人: John David Spencer
• 金额: $ 34.2万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-03 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9523793
• 关键词: AKT Signaling Pathway; Acute Renal Failure with Renal Papillary Necrosis; Affect; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacteremia; Caring; Cells; Cessation of life; Data; Defense Mechanisms; Diabetes Mellitus; Disease; Epithelial Cells; Foundations; Genetic Transcription; Goals; Health; Host Defense; Human; Hyperglycemia; Immune; Impairment; In Vitro; Infection; Infection prevention; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Intercalated Cell; Kidney; Knowledge; Laboratories; Link; Mediating; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Outcome; PI3K/AKT; Pancreatic ribonuclease; Phosphotransferases; Play; Prediabetes syndrome; Predisposition; Process; Production; Property; Publishing; Regulation; Research; Ribonucleases; Risk; Role; Site; Stream; Transgenic Mice; Transgenic Organisms; Urinary tract; Urinary tract infection; Uropathogen; Uropathogenic E. coli; Urothelium; Vertebrates; antimicrobial; antimicrobial peptide; bactericide; diabetic patient; experimental study; fighting; humanized mouse; improved; in vivo; insight; insulin signaling; kidney infection; microbial; mouse model; novel; novel therapeutics; prevent; renal abscess; urinary

ABSTRACT Diabetes mellitus is a systemic disorder that increases infection susceptibility. The most common site of infection is the urinary tract. Urinary tract infection (UTI) is more common, more severe, and has worse outcomes in people with diabetes. To date, the mechanisms that predispose people with diabetes to UTI have not been elucidated. This project will evaluate how insulin regulates innate immune mechanisms in the kidney’s intercalated cells. Surmounting evidence from our research group and others suggests that intercalated cells (IC) play a critical role in antibacterial defenses against uropathogenic E. coli (UPEC). Our research shows that insulin resistance and Type 2 diabetes mellitus increases UTI risk. When the insulin receptor is selectively deleted in murine ICs, UPEC susceptibility significantly increases in vivo. Also, we have demonstrated that insulin induces antimicrobial peptide (AMP) expression in primary human renal epithelial cells via the phosphatidylinositide 3-kinase (PI3K/AKT) signaling pathway. Specifically, our data show that insulin induces Ribonuclease 7 (RNase 7) production, the most potent AMP in the human urinary tract, to shield the urothelium from UPEC. Together, these data provide strong support for our hypothesis that insulin signaling plays an essential role in innate IC defenses by regulating PI3K/AKT activity and downstream AMP production. Building on these previous studies, we propose a comprehensive analysis of insulin’s ability to regulate IC defense mechanisms. Aim 1 will evaluate how insulin resistance and Type 2 diabetes mellitus affects IC antibacterial defenses. Aim 2 will identify how IC insulin receptor deletion impacts AMP transcription and whether targeted PI3K/AKT activation induces AMP expression. Aim 3 will use a novel transgenic humanized mouse model to assess how insulin resistance and insulin therapy impacts the production of RNase 7 and its antimicrobial activity in vivo. The long-term objective of this project is to improve the care of diabetic patients with UTI by identifying novel therapeutic options. By evaluating the role of insulin signaling in host defense, completion of these Aims can have profound influence on the health of people with diabetes as they may develop insulin-signaling targets, like PI3K/AKT and RNase 7, as new therapeutics that prevent UTI, extending UTI treatment options beyond the scope of antibiotics.

抽象的 糖尿病是一种增加感染易感性的全身性疾病，最常见的感染部位是糖尿病。 尿路感染 (UTI) 在患有尿路感染的人群中更为常见、更为严重，且预后更差。 迄今为止，糖尿病患者易患尿路感染的机制尚未阐明。 评估胰岛素如何调节肾脏闰细胞的先天免疫机制。 我们的研究小组和其他人表明，嵌入细胞 (IC) 在抗菌防御中发挥着关键作用 我们的研究表明，胰岛素抵抗和 2 型糖尿病会增加尿路感染风险。 当小鼠 IC 中的胰岛素受体被选择性删除时，体内 UPEC 敏感性显着增加。 我们已经证明胰岛素诱导原代人肾上皮细胞中抗菌肽（AMP）的表达 具体来说，我们的数据表明胰岛素通过磷脂酰肌醇 3 激酶 (PI3K/AKT) 信号通路诱导。 核糖核酸酶 7 (RNase 7) 的产生是人体泌尿道中最有效的 AMP，可保护尿路上皮免受 总之，这些数据为我们的假设提供了强有力的支持，即胰岛素信号在其中发挥着重要作用。 通过调节 PI3K/AKT 活性和下游 AMP 生产来实现先天 IC 防御。 研究中，我们建议对胰岛素调节 IC 防御机制的能力进行全面分析，以评估目标 1。 胰岛素抵抗和 2 型糖尿病如何影响 IC 抗菌防御能力 Aim 2 将确定 IC 胰岛素如何发挥作用。 受体缺失会影响 AMP 转录以及靶向 PI3K/AKT 激活是否会诱导 AMP 表达。 将使用新型转基因人源化小鼠模型来评估胰岛素抵抗和胰岛素治疗如何影响 RNase 7 的生产及其体内抗菌活性 该项目的长期目标是改善护理。 通过评估胰岛素信号在宿主中的作用，确定新的治疗方案，以治疗患有尿路感染的糖尿病患者。 防御，完成这些目标可能会对糖尿病患者的健康产生深远的影响，因为他们可能会发展 胰岛素信号靶标，如 PI3K/AKT 和 RNase 7，作为预防 UTI 的新疗法，延长 UTI 治疗 超出抗生素范围的选择。