Formyl peptide receptors as mediators of intestinal mucosal homeostasis

甲酰基肽受体作为肠粘膜稳态调节剂

基本信息

批准号：
8066189
负责人：
ASMA NUSRAT
金额：
$ 49.53万
依托单位：
EMORY UNIVERSITY
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：
2011-09-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8066189
关键词：
Actins Acute Agonist Annexins Anti-Inflammatory Agents Anti-inflammatory Apoptosis Bacteria Biochemical Biological Biological Process Chemicals Clinical Complex Coupled Development Disease Drug or chemical Tissue Distribution Enteral Environment Epithelial Epithelial Cell Proliferation Epithelial Cells Epithelium Epitopes Event FPR1 gene Family member Focal Adhesion Kinase 1 GTP-Binding Proteins Generations Growth Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Homeostasis Imaging Techniques Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Injury Intestinal Mucosa Intestines Ischemia Knockout Mice Laboratories Ligands Lipids MAP Kinase Gene Maintenance Mechanics Mediating Mediator of activation protein Microbe Modification Molecular Monoclonal Antibodies Mucositis NADPH Oxidase Natural regeneration Operative Surgical Procedures Outcome Oxidation-Reduction Pathogenesis Pathologic Pathway interactions Patients Pattern recognition receptor Peptides Phagocytes Physiological Processes Play Post-Translational Protein Processing Process Production Proliferating Property Protein Tyrosine Phosphatase Proteins Proteomics Reactive Oxygen Species Receptor Activation Receptor Signaling Recovery Regulation Resolution Role Signal Pathway Signal Transduction Site-Directed Mutagenesis Spatial Distribution Surface Therapeutic Therapeutic Agents Tissues cell motility fMet-Leu-Phe receptor formyl peptide gastrointestinal epithelium in vivo intestinal epithelium lipoxin A4 migration molecular imaging mouse model novel protein complex receptor response to injury small molecule wound

项目摘要

DESCRIPTION (provided by applicant): The gastrointestinal epithelium functions as a dynamic barrier that serves as an interface between luminal contents and underlying tissue compartments, and is thus vital in maintaining mucosal homeostasis. Mucosal wounds have been observed following enteric infection, inflammatory bowel disease and ischemic insults. Disruption of the critical epithelial barrier allows access of luminal contents to immunologically privileged compartments thereby contributing to disease pathogenesis. In response to injury, intestinal epithelial cells (IEC) migrate and proliferate to rapidly cover denuded surfaces and re-establish the epithelia barrier. We have recently identified expression of the N-formyl peptide receptors (FPR1 and FPR2) in the intestinal epithelium. Our studies determined that a bacterial derived N-formyl peptide, fMLF and the endogenous Annexin 1 protein, which are agonists for FPR family members, promote intestinal epithelial cell migration and facilitate wound closure. Additionally, it is becoming evident that a healthy optimized intestinal microflora mediates important roles in normal gut homeostasis and recovery from mucosal insults. Recent experimental results in our laboratory revealed that epithelial cells exposed to fMLF and intact bacteria also rapidly initiate cytoplasmic signaling events, Rac and Cdc2 activation, reactive oxygen species (ROS) production, epithelial cell migration and wound closure. Thus, we believe that FPRs represent important novel type of pattern recognition receptors (PRR) in the intestinal epithelium that transmit homeostatic signaling and facilitate epithelial barrier recovery following pathologic insults. Thus, our overall objectives are to define the pathobiologic function of epithelial FPRs and microbiota in regulating intestinal homeostasis, barrier recovery and resolution of inflammation. PUBLIC HEALTH RELEVANCE: Intestinal epithelial injury occurs in a wide spectrum of clinical conditions that include inflammatory bowel diseases, enteric infection, ischemia and following surgical procedures. The loss of epithelial barrier function associated with injury contributes to mucosal inflammation. Numerous physiological processes including those influenced by the normal prokaryotic microbiota have been implicated in regulating intestinal epithelial homeostasis. Thus, given the pathologic ramifications of epithelial injury, it is vital to understand mechanisms of intestinal epithelial barrier maintenance/recovery and in defining the role of microbiota in these processes. We propose the formyl peptide receptors (FPRs) as novel pattern recognition receptors that regulate intestinal epithelial growth, motility and restitution post injury, as well as the positive influence of the microbiota in these events. Realization of the role of FPRs and their ligands on epithelial barrier regulation and wound recovery will facilitate in development of therapeutic agents to promote regeneration of the intestinal mucosa.

描述（由申请人提供）：胃肠上皮的功能充当动态屏障，它是腔内内容物和基础组织室之间的界面，因此对于维持粘膜稳态至关重要。肠道感染，炎症性肠病和缺血性损伤后，已经观察到粘膜伤口。临界上皮屏障的破坏允许将腔内容物访问免疫特权隔室，从而有助于疾病发病机理。为了响应损伤，肠上皮细胞（IEC）迁移并增殖至迅速覆盖的表面并重新建立上皮屏障。我们最近鉴定了肠上皮中N-甲基肽受体（FPR1和FPR2）的表达。我们的研究确定，细菌衍生的N-甲基甲基肽FMLF和内源性膜剂1蛋白是FPR家族成员的激动剂，促进肠上皮细胞迁移并促进伤口闭合。此外，越来越明显的是，健康优化的肠道菌群在正常的肠道稳态中介导了重要的作用，并从粘膜损伤中恢复。我们实验室的最新实验结果表明，暴露于FMLF和完整细菌的上皮细胞也迅速引发了细胞质信号事件，RAC和CDC2激活，活性氧（ROS）产生，上皮细胞迁移和伤口闭合。因此，我们认为FPR代表了肠上皮中重要的新型模式识别受体（PRR），该类型是在病理侮辱后传递稳态信号传导并促进上皮屏障恢复的重要类型。因此，我们的总体目标是定义上皮FPR和微生物群在调节肠道稳态，障碍恢复和炎症的分辨率方面的病理生物学功能。公共卫生相关性：肠上皮损伤发生在各种临床疾病中，包括炎症性肠病，肠道感染，缺血以及遵循手术程序。与损伤相关的上皮屏障功能的丧失会导致粘膜炎症。许多生理过程，包括受正常核核微生物群影响的生理过程已与调节肠上皮稳态有关。因此，鉴于上皮损伤的病理影响，了解肠上皮屏障维持/恢复的机制以及定义微生物群在这些过程中的作用时至关重要。我们将甲基肽受体（FPR）作为新型模式识别受体，这些受体调节肠上皮生长，运动能力和损伤后的恢复性，以及在这些事件中菌群的积极影响。 FPR及其配体在上皮屏障调节和伤口恢复方面的作用的实现将有助于开发治疗剂，以促进肠粘膜再生。