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家园。这种精细平衡的破坏导致肠道炎症，这是世界范围内发病率和死亡率的重要原因。特发性炎症性肠病（IBD）在发达国家造成了重大的健康和经济负担，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20亿例疟疾病例和150万例死亡，主要是儿童。腹泻病原体如鼠伤寒沙门氏菌引起炎性腹泻，其模拟IBD的几个临床标志，包括大量中性粒细胞浸润到肠中。因此，了解疾病过程中驱动中性粒细胞浸润的共同机制对于预防和治疗疾病至关重要。 公共卫生肝氧素A3（HXA 3）是从沙门氏菌感染的上皮细胞的顶端表面分泌的生物活性脂质，其已被鉴定为是一种重要的和特异性的介导剂， 肠中的中性粒细胞跨上皮迁移。还发现HXA 3在由多种刺激以及炎症反应引发的肠道炎症期间驱动嗜中性粒细胞浸润。 在肺部炎症期间。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HXA 3介导的迁移的活性，我们称之为AMEND（活性调节上皮-中性粒细胞话语），现在已知是内源性大麻素家族成员。在本提案中，我们将检验以下假设：肠道中AMEND和HXA 3活性之间的平衡调节了诱导肠道炎症必须克服的稳态设定点。因此，我们试图进一步了解HXA 3和中性粒细胞之间的相互作用，并研究AMEND调节HXA 3活性在稳态和疾病的机制。在具体目标1中，我们将研究HxA 3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。这种方法旨在研究HxA 3和AMEND在特定PMN受体或代谢途径上竞争的程度，或独立协调对立机制的程度。在具体目标2中，将探索粘膜对促炎和抗炎脂质介质的调节和释放。具体来说，我们将研究HxA 3/MRP 2通路如何在功能失调的AMEND/P-gp通路的背景下驱动炎症。因此，我们将进行体外研究，以研究AMEND抵消HxA 3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，我们将确定药物在MRP 2/Pgp系统调节中的作用。该提议基于这样的概念，即在抑制对肠道细菌的反应的途径与激活对病原体/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，肠道微生物群影响IEC稳态的调节Pgp。在那里，我们将研究Pgp的神经调节控制是否会导致抑制性生物活性脂质的流出，即在控制健康与疾病之间的战斗中至关重要的AMEND。总之，这里提出的研究将大大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和治疗进展，在肠道生物学和病理学。