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

• 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
• 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

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）：胃肠上皮作为动态屏障发挥作用，作为腔内容物和下层组织隔室之间的界面，因此对维持粘膜稳态至关重要。在肠道感染、炎症性肠病和缺血性损伤后观察到粘膜损伤。关键上皮屏障的破坏允许管腔内容物进入免疫特权区室，从而有助于疾病的发病机制。肠上皮细胞（IEC）对损伤的反应是迁移和增殖，以迅速覆盖裸露的表面并重建上皮屏障。我们最近发现的N-甲酰肽受体（FPR 1和FPR 2）在肠上皮细胞的表达。我们的研究确定，细菌衍生的N-甲酰肽，fMLF和内源性膜联蛋白1蛋白，这是FPR家族成员的激动剂，促进肠上皮细胞迁移和促进伤口闭合。此外，越来越明显的是，健康的优化的肠道微生物菌群介导正常肠道稳态和从粘膜损伤中恢复的重要作用。我们实验室最近的实验结果表明，暴露于fMLF和完整细菌的上皮细胞也迅速启动细胞质信号传导事件，Rac和Cdc 2激活，活性氧（ROS）的产生，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），其传递稳态信号并促进病理损伤后上皮屏障的恢复。因此，我们的总体目标是确定上皮FPR和微生物群在调节肠内稳态、屏障恢复和炎症消退中的病理生物学功能。 公共卫生相关性：肠上皮损伤发生在广泛的临床病症中，包括炎性肠病、肠道感染、缺血和外科手术后。与损伤相关的上皮屏障功能丧失会导致粘膜炎症。许多生理过程，包括那些正常的原核微生物群的影响已经涉及到调节肠上皮细胞的稳态。因此，鉴于上皮损伤的病理后果，理解肠上皮屏障维持/恢复的机制以及确定微生物群在这些过程中的作用至关重要。我们提出甲酰肽受体（FPRs）作为新型模式识别受体，调节肠上皮细胞的生长，运动和损伤后的恢复，以及这些事件中微生物群的积极影响。认识到FPR及其配体在上皮屏障调节和创伤恢复中的作用将有助于开发促进肠粘膜再生的治疗剂。