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Intestinal Inflammation Orchestrated by Pathogens

由病原体精心策划的肠道炎症

基本信息

批准号：
9147569
负责人：
Beth A McCormick
金额：
$ 35.5万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-22 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9147569
关键词：
Acute Address Affect Anti-Inflammatory Agents Anti-inflammatory Apical Area Bacteria Biological Factors Biology Cartoons Cells Cessation of life Chemotaxis Child Clinical Colitis Complex Crohn&apos s disease Diarrhea Dietary Component Disease Elements Endocannabinoids Environment Epithelial Epithelial Cells Epithelium Equilibrium Event Family member Flare Genetic Goals Healed Health Home environment Homeostasis Host Defense Human Immigration Immune response In Vitro Individual Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Injury Intestinal Mucosa Intestines Invaded Ions Lead Learning Lipids Lung Inflammation Mechanics Mediating Mediator of activation protein Medicine Metabolic Pathway Methods Modification Morbidity - disease rate Movement Mucous Membrane Neutrophil Infiltration Outcome P-Glycoprotein Pathology Pathway interactions Patients Play Population Process Production Public Health Recruitment Activity Regulation Research Resolution Role Salmonella Salmonella typhimurium Signal Transduction Signaling Molecule Stimulus Sum Surface System Testing Therapeutic Tight Junctions Tissues Translating Ulcerative Colitis Variant anandamide base clinical application commensal microbes design efflux pump emergency service responder gut microbiota healing in vivo intestinal epithelium lipid mediator microbial microbicide microbiome microorganism migration mortality neutrophil novel novel therapeutics pathogen pathogenic bacteria receptor response solute

项目摘要

DESCRIPTION (provided by applicant): The human intestine is home to a continuous balancing act between the host immune response, the large population of resident bacteria, and the thin epithelial layer that separates them. Disruptions in this fine balance lead to intestinal inflammation, a significant cause of morbidity and mortality worldwide. The idiopathic inflammatory bowel diseases (IBD) impose a significant health and monetary burden in the developed world, with roughly 1 in 200 people in the US affected. In the developing world, infection with microbial pathogens leads to about two billion cases of diarrheal disease annually and 1.5 million deaths, primarily among children. Diarrheal pathogens such as Salmonella Typhimurium cause inflammatory diarrhea that mimics several clinical hallmarks of IBD including massive neutrophil infiltration into the intestine. Understanding the shared mechanisms that drive neutrophil infiltration during disease is therefore of critical importance in public health. Hepoxilin A3 (HXA3) is a bioactive lipid secreted from the apical surface of Salmonella-infected epithelial cells that has been identified as a crucial and specific mediator of neutrophil transepithelial migration in the intestine. HXA3 has also been found to drive neutrophil infiltration during intestinal inflammation triggered by a variety of stimuli as well as during lung inflammation. In addition, we have recently identified an activity secreted by uninfected epithelial cells that inhibit HXA3-mediated migration, which we refer to as AMEND (activity modulating epithelial-neutrophil discourse) and now known to be endocannabinoid family members. In this proposal, we will test the hypothesis that the balance between AMEND and HXA3 activity in the intestine regulates the homeostatic set point that must be overcome for the induction of intestinal inflammation. Thus, we seek to further understand the interaction between HXA3 and neutrophils, and to investigate the mechanisms by which AMEND regulates HXA3 activity during homeostasis and disease. In Specific Aim 1 we will examine the potential for HxA3 and AMEND to affect receptors and regulate intracellular pathways that control directed PMN transmigration. This approach is designed to examine the extent to which HxA3 and AMEND compete at specific PMN receptors, or metabolic pathways, or act independently to coordinate opposing mechanisms. In Specific Aim 2 the regulation and release of pro- and anti-inflammatory lipid mediators by the mucosa will be explored. Specifically, we will examine how the HxA3/MRP2 pathway could drive inflammation in the context of a dysfunctional AMEND/P-gp pathway. Thus, we will perform in vitro studies to investigate the mechanism by which AMEND counteracts HxA3 activity, and will evaluate the presence/function of AMEND in vivo. Finally, in Specific Aim 3 we will determine the role of commensals in the regulation of the MRP2/Pgp systems. This proposal is based on the concept that there is a dynamic relationship between pathways that suppress responses to commensal bacterial and pathways that activate responses to pathogens/aberrant signals. Our preliminary studies suggest that the intestinal microbiota influence IEC homeostasis in the regulation of Pgp. There, we will examine whether a commensal-regulated control of Pgp results in the efflux of suppressive bioactive lipids, namely AMEND that will be important in controlling the battle between health vs disease. In sum, the studies proposed here will contribute greatly to understanding the basic biology of the epithelium and its ability to control neutrophil recruitment, opening up further research avenues and therapeutic advancement in intestinal biology and pathology.