Polarity proteins and intestinal mucosal responses to inflammation and injury

极性蛋白和肠粘膜对炎症和损伤的反应

基本信息

批准号：
10598126
负责人：
ASMA NUSRAT
金额：
$ 50.27万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598126
关键词：
Actins Address Adherens Junction Adhesions Adhesives Apical Attenuated Binding Biological Process Biopsy Cell membrane Cell-Matrix Junction Clinical Colon Complement Complex Crohn&apos s disease Cytoplasm Cytoskeleton Data Development Disease Epithelial Cells Epithelium Event F-Actin Family member Gastrointestinal tract structure Goals Grant Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Homeostasis Human IL17 gene Immune Immunity In Vitro Individual Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Injury Integral Membrane Protein Intercellular Junctions Interferon Type II Intestinal Mucosa Intestines Invertebrates Ischemia Knowledge Link Malignant Neoplasms Mammals Mechanics Mediating Membrane Modeling Molecular Mucous Membrane Mus Neurofibromin 2 Operative Surgical Procedures Pathogenesis Pathologic Persons Play Protein Family Proteins Reagent Recovery Regulation Role Scaffolding Protein Signal Transduction TNF gene Tertiary Protein Structure Tight Junctions Transformed Cell Line Transgenic Mice apical membrane cell motility cytokine epithelial injury epithelial repair epithelial wound experimental study gastrointestinal epithelium genetic regulatory protein healing in vivo insight intestinal barrier intestinal epithelium knock-down link protein migration model organism novel novel therapeutic intervention protein complex protein expression recruit repair model repaired response rho rho GTP-Binding Proteins stem cells two-dimensional wound wound closure wound healing

项目摘要

Abstract The gastrointestinal epithelium plays a central role in maintaining barrier function while coordinating mucosal homeostasis and immunity. An important negative consequence of excessive inflammation, ischemia, certain infections, and other clinical conditions is mucosal epithelial injury and wounding that serves to compromise the epithelial barrier which is tightly regulated by intercellular junctions that include the tight junction (TJ) and adherens junction (AJ), collectively referred to as the Apical Junctional Complex (AJC). Proteins involved in regulating epithelial polarity such as the Crumbs family of proteins, influence organization and function of the AJC and regulate epithelial homeostasis and differentiation. Since most of studies on polarity proteins have been performed in model organisms and transformed cell lines, current knowledge of the molecular basis by which polarity proteins orchestrate intestinal epithelial barrier function and wound repair in vivo in mammals remains limited. The overall goal of this proposal is to identify how the polarity protein Crumbs 3 (CRB3) controls epithelial homeostasis, namely barrier function and wound repair in vivo using CRB3 transgenic mice and natural human and murine intestinal epithelium. Our overarching hypothesis is that CRB3 functions as a master regulator of intestinal epithelial barrier function and wound repair by controlling assembly of different adhesion-cytoskeletal modules at the plasma membrane. Knowledge gained from these studies in the short term will provide important new insights on basic mechanisms by which polarity proteins regulate the intestinal epithelial barrier and repair. In the long term, these studies will likely provide ideas for development of new therapeutic strategies aimed at strengthening the epithelial barrier and in promoting intestinal mucosal wound repair.

抽象的胃肠道上皮在维持屏障功能、协调粘膜功能方面发挥着核心作用。体内平衡和免疫力。过度炎症、缺血、某些感染和其他临床病症是粘膜上皮损伤和创伤，这会损害上皮屏障受到细胞间连接的严格调节，包括紧密连接（TJ）和粘附连接（AJ），统称为顶端连接复合体（AJC）。参与蛋白质调节上皮极性，例如 Crumbs 蛋白家族，影响细胞的组织和功能 AJC 并调节上皮稳态和分化。由于大多数关于极性蛋白的研究都已在模型生物体和转化细胞系中进行，目前的分子基础知识哪些极性蛋白在哺乳动物体内协调肠上皮屏障功能和伤口修复仍然有限。该提案的总体目标是确定极性蛋白 Crumbs 3 (CRB3) 如何使用 CRB3 转基因小鼠体内控制上皮稳态，即屏障功能和伤口修复以及天然的人类和小鼠肠上皮。我们的总体假设是 CRB3 的功能是通过控制不同的组装来控制肠上皮屏障功能和伤口修复质膜上的粘附细胞骨架模块。短期内从这些研究中获得的知识该术语将为极性蛋白调节肠道的基本机制提供重要的新见解。上皮屏障和修复。从长远来看，这些研究可能会为新产品的开发提供思路。旨在加强上皮屏障和促进肠粘膜伤口的治疗策略维修。