Intestinal Inflammation Orchestrated by Pathogens

由病原体精心策划的肠道炎症

• 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
• 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' 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

 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.

 描述(由申请人提供)：人体肠道是宿主免疫反应、大量常驻细菌和分隔它们的薄上皮层之间持续平衡的场所。这种微妙平衡的破坏会导致肠道炎症，这是全球发病率和死亡率的一个重要原因。特发性炎症性肠病(IBD)在发达国家造成了巨大的健康和金钱负担，在美国，大约每200人中就有1人受到影响。在发展中国家，微生物病原体感染每年导致约20亿腹泻病例和150万人死亡，其中主要是儿童。腹泻病原体，如鼠伤寒沙门氏菌，会引起炎症性腹泻，这与IBD的几个临床特征相似，包括大量中性粒细胞渗入肠道。因此，了解在疾病过程中驱动中性粒细胞渗透的共同机制在 公共卫生。海波西林A3(HXA3)是一种从沙门氏菌感染的上皮细胞顶面分泌的生物活性脂质，已被认为是沙门氏菌感染的关键和特异的介体。 中性粒细胞在肠道内的跨上皮迁移。HXA3还被发现在各种刺激引发的肠道炎症过程中促进中性粒细胞的渗透 在肺部发炎期间。此外，我们最近发现了一种由未感染的上皮细胞分泌的抑制HXA3介导的迁移的活性，我们将其称为ADMAND(活性调节上皮-中性粒细胞话语)，现在已知它是内源性大麻素家族成员。在这项提案中，我们将检验这一假设，即肠道中ADMAND和HXA3活性之间的平衡调节必须克服的动态平衡设定点，以诱导肠道炎症。因此，我们试图进一步了解HXA3与中性粒细胞之间的相互作用，并探讨在体内平衡和疾病过程中，ADM调节HXA3活性的机制。在特定的目标1中，我们将研究HxA3的潜力，并修改以影响受体，并调节控制定向PMN转运的细胞内途径。这种方法被设计用来检查HxA3和Modify在多大程度上竞争特定的PMN受体或代谢途径，或者独立地作用于协调相反的机制。在特定目标2中，将探讨粘膜对促炎和抗炎脂质介质的调节和释放。具体地说，我们将研究HxA3/MRP2途径如何在功能失调的ADMAND/P-gp途径的背景下驱动炎症。因此，我们将进行体外研究，以探讨ADMAND抑制HxA3活性的机制，并将评估ADMAND在体内的存在/功能。最后，在具体目标3中，我们将确定共生关系在调节MRP2/PGP系统中的作用。这一建议是基于这样一个概念，即在抑制对共生细菌的反应的途径和激活对病原体/异常信号的反应的途径之间存在动态关系。我们的初步研究表明，肠道微生物区系在Pgp的调节中影响IEC的动态平衡。在那里，我们将检验Pgp的共生调节控制是否导致抑制性生物活性脂质的外流，即修正这一点，这将在控制健康与疾病之间的斗争中发挥重要作用。综上所述，本文提出的研究将有助于了解上皮细胞的基本生物学及其控制中性粒细胞募集的能力，开辟进一步的研究途径，并在肠道生物学和病理学方面取得治疗进展。