The role of ErbB3-induced Pmp22 in intestinal barrier function

ErbB3诱导的Pmp22在肠道屏障功能中的作用

基本信息

批准号：
10675038
负责人：
Jonathan Jay Hsieh
金额：
$ 4.77万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10675038
关键词：
Action Potentials Adolescent Affect American Apoptosis Celiac Disease Cell Line Cell-Matrix Junction Cells Child Chronic Code Data Development Disease Down-Regulation ERBB2 gene Epidermal Growth Factor Receptor Epithelial Cells Epithelium ErbB Receptor Family Protein ErbB4 gene Experimental Designs Family member Functional disorder Health Heterodimerization Impairment Incidence Inflammatory Inflammatory Bowel Diseases Injury Intestinal Diseases Intestinal permeability Intestines Intraperitoneal Injections Irritable Bowel Syndrome Knowledge Leaky Gut Ligands Lung MAP Kinase Gene Maintenance Molecular Mus Myelin Myelin Sheath NRG1 gene Natural regeneration Neuregulins Organ Organoids PIK3CG gene PMP22 gene Pathology Pathway interactions Peripheral Nerve Sheath Peripheral Nerves Permeability Personal Satisfaction Play Publishing Receptor Protein-Tyrosine Kinases Regulation Research Rest Role Sampling Schwann Cells Signal Transduction Testing Tight Junctions Tissues Transfection Water Work airway epithelium cell growth epithelial repair gut health intestinal barrier intestinal epithelium knock-down member microbiota monolayer novel therapeutic intervention nutrient absorption overexpression protein expression receptor repaired restraint seal small molecule stem cells therapeutic target

项目摘要

PROJECT SUMMARY/ABSTRACT The intestinal epithelium is critical in the maintenance of gut health and function. It absorbs nutrients and water, while also acting as a barrier to separate luminal contents and the microbiota from the rest of the body. Intestinal stem cells (ISCs) are central to the formation and regeneration of this barrier. Barrier dysfunction is associated with diseases such as inflammatory bowel disease, celiac disease, and irritable bowel syndrome. Despite the importance it has in intestinal disorders, there are currently no treatments that target the barrier. My preliminary data suggest that the ErbB3 receptor tyrosine kinase is important in maintenance of this barrier, as mice with ErbB3 deletion in the intestinal epithelium (ErbB3-IEKO) have increased intestinal permeability. Previous studies implicated ErbB3 and its ligand Nrg-1β as important factors in epithelial barriers, as Nrg-1β promotes tight junction formation in airway epithelial cells; however, ErbB3’s role in maintenance of the intestinal barrier is as yet poorly understood. We find that ErbB3-IEKO mice have markedly reduced expression of Pmp22, a component of epithelial tight junctions originally described as in the myelin sheath of peripheral nerves. In this project, I will test the hypothesis that ErbB3 promotes tight junction formation and maintenance in the intestinal epithelium through induction of Pmp22. In the first aim, I will define the role of Pmp22 in regulating tight junctions in the intestinal epithelium. This will be done through intestinal epithelial cell lines with Pmp22 knocked down or overexpressed via transfection, and mice given intraperitoneal injection of Nrg-1β to induce Pmp22 expression. In the second aim, I will determine how Pmp22 is regulated in the epithelium through the use of the small molecules inhibiting pathways downstream of ErbB3 in intestinal epithelial cells. Because ErbB3 requires a heterodimerization partner for signaling, I will also determine which ErbB family members are required for EbB3-driven Pmp22 expression. The proposed research will advance knowledge of how the intestinal barrier is formed and regulated, and ultimately will work towards developing barrier maintenance as a therapeutic target for inflammatory diseases in the gut.

项目概要/摘要肠上皮对于维持肠道健康和功能至关重要，它吸收营养并发挥作用。水，同时也充当将管腔内容物和微生物群与身体其他部分分开的屏障。肠道干细胞（ISC）对于屏障功能障碍的形成和再生至关重要。与炎症性肠病、乳糜泻和肠易激综合征等疾病有关。尽管它在肠道疾病中很重要，但目前还没有针对该屏障的治疗方法。我的初步数据表明 ErbB3 受体酪氨酸激酶对于维持这一屏障很重要，肠上皮细胞 ErbB3 缺失的小鼠 (ErbB3-IEKO) 肠道通透性增加。先前的研究表明 ErbB3 及其配体 Nrg-1β 是上皮屏障的重要因素，如 Nrg-1β 促进气道上皮细胞紧密连接的形成；然而，ErbB3 在维持气道上皮细胞中的作用我们对 ErbB3-IEKO 小鼠肠道屏障的了解仍知之甚少。 Pmp22 的表达，Pmp22 是上皮紧密连接的一个组成部分，最初被描述为存在于髓鞘中在这个项目中，我将测试 ErbB3 促进紧密连接形成和的假设。通过诱导 Pmp22 维持肠上皮细胞的功能在第一个目标中，我将定义 Pmp22 的作用。 Pmp22 调节肠上皮的紧密连接，这将通过肠上皮细胞来完成。通过转染敲低或过表达 Pmp22 的细胞系，以及腹膜内注射 Pmp22 的小鼠 Nrg-1β 诱导 Pmp22 表达在第二个目标中，我将确定 Pmp22 在细胞中的调控方式。通过使用小分子抑制肠道中 ErbB3 下游的上皮细胞因为 ErbB3 需要异源二聚体来进行信号传导，所以我还将确定是哪个。 ErbB 家族成员是 EbB3 驱动的 Pmp22 表达所必需的。拟议的研究将取得进展。了解肠道屏障如何形成和调节，并最终致力于开发屏障维持作为肠道炎症性疾病的治疗目标。