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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：
10442201
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/10442201
关键词：
Actins Address Adherens Junction Adhesions Adhesives Animal Model Apical Attenuated Binding Biological Process Biopsy Cell membrane Cell-Matrix Junction Clinical Complement Complex Crohn&apos s disease Cytoskeleton Data Development Disease Epithelial Epithelial Cells Event F-Actin Family member Gastrointestinal tract structure Goals Grant Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Homeostasis Human Immune Immunity In Vitro Individual Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Injury Integral Membrane Protein Intercellular Junctions Interferon Type II Interleukin-17 Intestinal Mucosa Intestines Invertebrates Ischemia Knowledge Link Longitudinal Studies Malignant Neoplasms Mammals Mechanics Mediating 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 base 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 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.

摘要胃肠道上皮在维持屏障功能同时协调粘膜功能方面起着重要作用。体内平衡和免疫力。一个重要的负面后果过度炎症，缺血，某些感染和其他临床病症的最大障碍是粘膜上皮损伤和创伤，其用于损害上皮屏障由细胞间连接紧密调节，包括紧密连接（TJ）和粘附连接（AJ），统称为顶端连接复合体（AJC）。蛋白参与调节上皮极性，如Crumbs蛋白家族，影响上皮细胞的组织和功能。 AJC和调节上皮稳态和分化。由于大多数关于极性蛋白的研究在模式生物和转化细胞系中进行，目前的分子基础知识，所述极性蛋白在哺乳动物体内协调肠上皮屏障功能和创伤修复仍然有限。该提案的总体目标是确定极性蛋白Crumbs 3（CRB3）使用CRB3转基因小鼠在体内控制上皮稳态，即屏障功能和伤口修复和天然的人和鼠的肠上皮。我们的总体假设是CRB3作为一种掌握调节肠上皮屏障功能和伤口修复的控制组装的不同粘附细胞骨架模块在质膜。在短期内从这些研究中获得的知识术语将提供重要的新见解的基本机制，极性蛋白质调节肠道上皮屏障和修复。从长远来看，这些研究可能会为开发新的治疗策略旨在加强上皮屏障和促进肠粘膜损伤修复.