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）：人类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，这种良好平衡的破坏会导致肠道炎症，这是一种肠道炎症。特发性炎症性肠病 (IBD) 是导致全球发病和死亡的重要原因，给发达国家带来了巨大的健康和经济负担，美国大约有二百分之一的人受到影响。在世界范围内，微生物病原体感染每年导致约 20 亿例腹泻病例和 150 万人死亡，其中主要是儿童。鼠伤寒沙门氏菌等腹泻病原体会引起炎症性腹泻，其症状与 IBD 的多种临床特征相似，包括大量中性粒细胞浸润肠道。因此，疾病期间驱动中性粒细胞浸润的共同机制至关重要 赫泊西林 A3 (HXA3) 是一种从沙门氏菌感染的上皮细胞顶端表面分泌的生物活性脂质，已被确定为重要且特异性的介质。 还发现 HXA3 在肠道中的中性粒细胞跨上皮迁移可在各种刺激引发的肠道炎症期间驱动中性粒细胞浸润。 此外，我们最近发现了未感染的上皮细胞分泌的一种抑制 HXA3 介导的迁移的活性，我们将其称为 AMEND（调节上皮-中性粒细胞对话的活性），现在已知其为内源性大麻素家族成员。提案中，我们将测试肠道中 AMEND 和 HXA3 活性之间的平衡调节诱导肠道炎症必须克服的稳态设定点的假设。了解 HXA3 和中性粒细胞之间的相互作用，并研究 AMEND 在稳态和疾病期间调节 HXA3 活性的机制。在具体目标 1 中，我们将研究 HxA3 和 AMEND 影响受体和调节控制定向 PMN 迁移的细胞内途径的潜力。该方法旨在检查 HxA3 和 AMEND 在特定 PMN 受体或代谢途径上竞争的程度，或在特定目标中独立发挥作用以协调相反的机制。 2 具体来说，我们将探讨粘膜对促炎和抗炎脂质介质的调节和释放，从而研究 HxA3/MRP2 通路如何在 AMEND/P-gp 通路功能失调的情况下驱动炎症。我们将进行体外研究，以研究 AMEND 抵消 HxA3 活性的机制，并将评估 AMEND 在体内的存在/功能。最后，在具体目标 3 中，我们将确定共生体在调节中的作用。该提议基于以下概念：抑制共生细菌反应的途径与激活病原体/异常信号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群影响 IEC 稳态。在那里，我们将研究 Pgp 的共生调节控制是否会导致抑制性生物活性脂质的外流，即 AMEND，这对于控制健康与健康之间的斗争非常重要。总之，这里提出的研究将极大地有助于了解上皮的基本生物学及其控制中性粒细胞募集的能力，开辟肠道生物学和病理学的进一步研究途径和治疗进展。