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Intestinal Homeostasis Induced by Commensals

共生体诱导的肠道稳态

基本信息

批准号：
10212384
负责人：
Beth A McCormick
金额：
$ 56万
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：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10212384
关键词：
ABCB1 gene Acute Address Anti-Inflammatory Agents Apical Bile Acids Biological Biological Models Cells Colitis Communication Communities Complex Computing Methodologies Cues Data Disease Elements Endocannabinoids Environment Epithelial Epithelial Cells Equilibrium Ethanolamines Eubacterium Feces Foundations Functional disorder Gene Cluster Genes Genetic Genetic Transcription Goals Homeostasis Host Defense Human Immune system In Vitro Individual Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Injury Intervention Intestinal Mucosa Intestines Invaded Knowledge Lactobacillus Link Lipids Machine Learning Maintenance Mediating Metabolic Modeling Modification Molecular Mucous Membrane Multi-Drug Resistance Mus Outcome Output Pathway interactions Patients Pharmaceutical Preparations Phenotype Pilot Projects Play Process Public Health Pump Regulation Research Resolution Role Sentinel Severities Signal Transduction Structure Submucosa Surface System Testing Time Toxin Work Xenobiotic Metabolism arm bacterial community base commensal bacteria design efflux pump first responder healing host colonization host-microbe interactions in vivo inflammatory disease of the intestine innate immune mechanisms insight intestinal epithelium intestinal homeostasis mathematical model microbial microbiome microbiota microorganism migration mouse model neutrophil new therapeutic target normal microbiota novel novel therapeutic intervention nuclear factor 1 prevent recruit response theories transcriptomics

项目摘要

ABSTRACT While multidrug-resistance transporters including P-gp and MRP2 are generally studied for their role in exporting drugs and foreign compounds from the cell, our studies indicate that these efflux pumps expressed at the apical surface of intestinal epithelial cells provide a critical link in communication between sentinel functions of mucosal barriers and the immune system. Understanding how this P-gp/eCB anti-inflammatory arm is regulated will provide crucial insight into how dysfunction may promote intestinal inflammation and help identify potential new therapeutic targets. Because the resident microbiota is known to contribute to tolerance and homeostasis in the healthy intestine, the central hypothesis we aim to test is whether the normal microbiota actively drives the P-gp/eCB axis to prevent unnecessary inflammation. Our pilot studies indicate that the microbiota does influence P-gp expression and function, providing a unique foundation for further cause-effect studies. No data have previously demonstrated a link between the microbiota and eCBs or any other epithelial lipid signals, and may well provide great insight into a novel system. Bridging this gap could help explain how commensal bacteria can stabilize a state of tolerance and how genetic modification of specific pathway elements might predispose individuals to conditions of inflammatory bowel disease (IBD). To begin addressing these questions, in Aim 1 of this application will combine in vitro (including human colonoids) and in vivo murine model systems, as well as use healthy and UC patient stool, to more deeply understand the microbial consortia that collectively maximize P-gp expression and function. Aim 2 is designed to identify the microbial metabolites that drive activation of P-gp expression and eCB secretion to maintain an anti-inflammatory tone in the intestinal epithelium. Thus, transcriptomics and metabolite analyses will be performed to provide new information regarding microbial genes, gene clusters, and their metabolic products implicated in maintaining an anti- inflammatory tone in the intestinal epithelium through regulation of the P-gp/eCB axis. In Aim 3 we will employ novel computational methods will to uncover the inter-microbial network responses and the ecological structure of a stable community that is able to induce P-gp expression. Collectively, knowledge of the pathways that coordinate the maintenance of the P-gp/eCB axis will require a comprehensive understanding of distinct signals regulating intestinal homeostasis, how multiple signals are integrated in the complex intestinal environment, and pathways that modulate host-microbe interactions. Consequently, this proposal will directly advance novel biological principles with guidance of new therapeutic intervention strategies.

摘要