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：
10507774
负责人：
Jonathan Jay Hsieh
金额：
$ 4.68万
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/10507774
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 Epithelial Cells ErbB Receptor Family Protein ErbB4 gene 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 Nutrient Organ Organoids 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 design epithelial repair experimental study gut health intestinal barrier intestinal epithelium knock-down member microbiota monolayer novel therapeutic intervention overexpression protein expression receptor repaired 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.

项目摘要/摘要肠上皮对于维持肠道健康和功能至关重要。它吸收营养和水，同时还充当分离腔内含量和与身体其他部位的菌群的障碍。肠道干细胞（ISC）对于该屏障的形成和再生至关重要。屏障功能障碍是与炎症性肠病，乳糜泻和肠易激综合征等疾病有关。尽管它具有重要的肠道疾病，但目前尚无针对障碍的治疗方法。我的初步数据表明，ERBB3受体酪氨酸激酶对于维持这种障碍很重要，由于肠上皮（ERBB3-ieko）中具有ERBB3缺失的小鼠的肠道通透性增加。先前的研究将ERBB3及其配体NRG-1β作为上皮屏障的重要因素，为NRG-1β 促进气道上皮细胞中的紧密连接形成；但是，ERBB3在维护肠壁尚未理解。我们发现Erbb3-ieko小鼠显着减少了 PMP22的表达，PMP22是最初描述为髓鞘鞘的上皮紧密连接的组成部分周围神经。在这个项目中，我将检验以下假设：ERBB3促进了紧密的连接形成和通过诱导PMP22在肠上皮中维持。在第一个目标中，我将定义 PMP22在控制肠上皮细胞中的紧密连接处。这将通过肠上皮细胞完成通过转染击倒或过表达PMP22的线，腹膜内注射的小鼠 NRG-1β诱导PMP22表达。在第二个目标中，我将确定如何在上皮通过使用小分子抑制ERBB3下游肠道的途径上皮细胞。因为ERBB3需要一个异二聚化伙伴才能发出信号，所以我还将确定哪个 ERBB家庭成员是EBB3驱动的PMP22表达所必需的。拟议的研究将进步了解如何形成和调节肠壁的方式，并最终将致力于发展障碍物维持是肠道炎症性疾病的治疗靶标。