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

基本信息

批准号：
9883788
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
项目类别：
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/9883788
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 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 infection risk innate immune mechanisms insight insulin signaling kidney infection microbial mouse model novel novel therapeutics prevent renal abscess renal epithelium urinary

项目摘要

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系统性疾病，可提高感染敏感性。最常见的感染部位是尿路感染（UTI）更普遍，更严重，并且患有糖尿病。迄今为止，尚未阐明使糖尿病患者容易患糖尿病患者的机制。这个项目将评估胰岛素如何调节肾脏插入细胞中的先天免疫机制。从而从中获得证据我们的研究小组和其他研究小组表明，插入的细胞（IC）在抗菌防御措施中起着至关重要的作用肝病大肠杆菌（UPEC）。我们的研究表明，胰岛素抵抗和2型糖尿病会增加UTI风险。当在鼠IC中选择性地删除胰岛素受体时，UPEC易感性会显着增加体内。还，我们已经证明胰岛素在原代人肾上皮细胞中诱导抗菌胡椒（AMP）表达通过磷脂酰肌醇3-激酶（PI3K/AKT）信号通路。具体来说，我们的数据表明胰岛素会影响核糖核酸酶7（RNase 7）生产，是人类尿路中最潜在的放大器，以保护尿皮细胞免受 UPEC。这些数据共同为我们的假设提供了强有力的支持，即胰岛素信号在通过调节PI3K/AKT活动和下游放大器的生产来进行天生IC防御。以这些先前的为基础研究，我们提出了胰岛素调节IC防御机制能力的全面分析。 AIM 1将评估胰岛素抵抗和2型糖尿病如何影响IC抗菌防御。 AIM 2将确定IC胰岛素如何受体缺失会影响AMP转录以及靶向PI3K/AKT激活是否诱导AMP表达。目标3 将使用一种新型的转基因人源性小鼠模型来评估胰岛素抵抗和胰岛素治疗如何影响 RNase 7及其在体内的抗菌活性的产生。该项目的长期目标是改善护理通过鉴定新的治疗选择，患有UTI的糖尿病患者。通过评估胰岛素信号在宿主中的作用防御，这些目标的完成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，例如PI3K/AKT和RNase 7，作为预防UTI的新疗法，扩展了UTI治疗抗生素范围之外的选择。