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

• 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
• 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

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 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。 肠干细胞（ISC）对于这一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 肠道屏障目前仍知之甚少。我们发现 ErbB3-IEKO 小鼠的 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 周围神经。在这个项目中，我将检验 ErbB3 促进紧密连接形成的假设 通过诱导 Pmp22 维持肠上皮细胞。在第一个目标中，我将定义以下角色： Pmp22 调节肠上皮细胞的紧密连接。这将通过肠上皮细胞完成 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 通过使用小分子抑制肠道中 ErbB3 下游通路 上皮细胞。因为 ErbB3 需要异二聚化伙伴来进行信号传导，所以我还将确定哪个 ErbB 家族成员是 EbB3 驱动的 Pmp22 表达所必需的。拟议的研究将推进 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。