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（由适用提供）：人类肠道是宿主免疫反应，大量居民细菌和将它们分开的薄皮层之间连续平衡行为的所在地。这种良好平衡的破坏导致肠道感染，这是全球发病率和死亡率的重要原因。特发性炎症性肠道疾病（IBD）在发达国家施加了重要的健康和货币伯宁，美国大约有200人受到影响。在发展中国家，微生物病原体的感染每年导致大约20亿例腹泻病和150万例死亡，首先是儿童。腹泻病原体（例如沙门氏菌伤寒）引起炎症性腹泻，模仿了IBD的几种临床标志，包括大量嗜中性粒细胞浸润到肠道中。因此，了解在疾病期间驱动中性粒细胞浸润的共同机制在 公共卫生。肝素A3（HXA3）是从沙门氏菌感染的上皮细胞的顶部分泌的生物活性脂质，已被鉴定为至关重要的和特定的介体 肠中嗜中性粒细胞迁移。还发现HXA3在由多种刺激以及 在肺部感染期间。此外，我们最近确定了一项由未感染的上皮细胞分泌的活性，该活性抑制了HXA3介导的迁移，我们称之为修正（调节上皮性中性嗜性粒子话语），现在已知是内源性大麻素家族成员。在此提案中，我们将检验以下假设：肠道中修正和HXA3活性之间的平衡调节稳态设定点，这必须克服肠道感染的诱导。这是，我们寻求进一步了解HXA3与中性粒细胞之间的相互作用，并研究修改在体内稳态和疾病期间调节HXA3活性的机制。在特定目标1中，我们将检查HXA3的潜力，并修改影响受体并调节控制定向PMN传播的细胞内途径。该方法旨在检查HXA3并修改特定PMN受体或代谢途径的程度，或独立采取行动以协调相反的机制。在特定的目标2中，将探索粘膜促脂质脂质介质的调节和释放。具体而言，我们将研究HXA3/MRP2途径如何在功能失调的修正案/P-GP途径的情况下驱动注射。这就是我们将进行体外研究，以研究修正对HXA3活性的修改的机制，并评估体内修正的存在/功能。最后，在特定的目标3中，我们将确定共生在MRP2/PGP系统调节中的作用。该建议基于这样的概念，即抑制对共生细菌的反应和激活对病原体/异常信号反应的途径的途径之间存在动态关系。我们的初步研究表明，肠道微生物群在PGP调节中影响IEC稳态。在那里，我们将检查对PGP的共生控制是否会导致抑制性生物活性脂质的排出，即修正，这对于控制健康与疾病之间的战斗至关重要。总而言之，这里提出的研究将有助于理解上皮的基本生物学及其控制中性粒细胞募集的能力，开放进一步的研究途径和治疗。肠生物学和病理学的进步。