Regulation of Intestinal Tight Junction Structure by Membrane Traffic

膜交通对肠道紧密连接结构的调节

基本信息

批准号：
8039594
负责人：
Jean M Wilson
金额：
$ 37.88万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8039594
关键词：
Adult Antigens Apical Architecture Binding Cell Polarity Cellular Morphology Complex Cytoplasmic Tail Data Development Development Polarity Dominant-Negative Mutation Endosomes Enterocytes Epithelial Epithelial Cells Fibroblasts Generations Goals Immunity Inflammatory Bowel Diseases Integral Membrane Protein Intestines Investigation Laboratories Life Macromolecular Complexes Maintenance Malignant Neoplasms Mediating Membrane Membrane Glycoproteins Membrane Protein Traffic Modeling Monomeric GTP-Binding Proteins Necrotizing Enterocolitis Neonatal Neurons Newborn Infant Nutrient Organ Pathology Pathway interactions Permeability Phosphorylation Positioning Attribute Predisposition Proteins Rattus Regulation Role Scaffolding Protein Sorting - Cell Movement Structure Tight Junctions Work absorption apical membrane endotubin insight intestinal epithelium knock-down molecular marker mutant neonate novel pathogen research study synthetic peptide tool trafficking trans-Golgi Network

项目摘要

DESCRIPTION (provided by applicant): The establishment and maintenance of epithelial tight junction integrity is essential to the normal function of epithelial organs; above all, the ability of the intestinal epithelium to serve as a selective barrier to antigens and pathogens while absorbing nutrients is fundamental to intestinal function. Also, tight junctions together with associated polarity complexes are critical for the maintenance of epithelial polarity. Our investigations of epithelial development and polarity have focused on the endosomal protein, endotubin. Endotubin is an integral membrane protein that is resident in apical endosomes of polarized epithelial cells. It is expressed at high levels in developing intestine, particularly when the enterocytes are establishing polarity. Moreover, endotubin regulates junctional integrity and epithelial polarity, possibly through interaction with aPKC and Rab14. In this proposal, we will elucidate the mechanism of action of endotubin and Rab14 in the establishment and maintenance of epithelial tight junctions and polarity. Experiments outlined in this proposal will define the role of endotubin and Rab14 in targeting of junctional and apical proteins and elucidate the motifs of endotubin critical for the establishment and maintenance of epithelial junctions. Our hypothesis is that endotubin serves as a scaffolding protein to organize and target junctional and polarity proteins from the apical endosomes. Loss of endotubin function could result in loss of barrier function and/or apical-basolateral polarity, leading to compromised immunity in the newborn, increased susceptibility to inflammatory bowel disease, and/or cancer. PUBLIC HEALTH RELEVANCE: Maintenance of epithelial cell tight junctions is essential for intestinal epithelial barrier function. Understanding the role of membrane trafficking in the generation and maintenance of tight junctions is fundamental to our understanding of intestinal development, normal function, and pathology.

描述（申请人提供）：上皮紧密连接完整性的建立和维持对于上皮器官的正常功能至关重要；最重要的是，肠上皮在吸收营养物的同时作为抗原和病原体的选择性屏障的能力是肠道功能的基础。此外，紧密连接以及相关的极性复合物对于维持上皮极性至关重要。我们对上皮发育和极性的研究主要集中在内体蛋白内管蛋白上。内管蛋白是一种完整的膜蛋白，存在于极化上皮细胞的顶端内体中。它在发育中的肠道中高水平表达，特别是当肠上皮细胞建立极性时。此外，内管蛋白可能通过与 aPKC 和 Rab14 相互作用来调节连接完整性和上皮极性。在本提案中，我们将阐明内管蛋白和 Rab14 在建立和维持上皮紧密连接和极性方面的作用机制。该提案中概述的实验将定义内管蛋白和 Rab14 在靶向连接和顶端蛋白中的作用，并阐明内管蛋白对于上皮连接的建立和维持至关重要的基序。我们的假设是内管蛋白作为支架蛋白来组织和靶向来自顶端内体的连接蛋白和极性蛋白。内管蛋白功能丧失可能导致屏障功能和/或顶端-基底外侧极性丧失，导致新生儿免疫力受损，增加对炎症性肠病和/或癌症的易感性。公众健康相关性：上皮细胞紧密连接的维持对于肠上皮屏障功能至关重要。了解膜运输在紧密连接的产生和维持中的作用对于我们理解肠道发育、正常功能和病理学至关重要。