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METABOLIC REGULATION OF INFLAMMATION BY MICROBIAL-DERIVED SHORT CHAIN FATTY ACIDS

微生物衍生的短链脂肪酸对炎症的代谢调节

基本信息

批准号：
9242634
负责人：
Sean P Colgan
金额：
$ 34.66万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9242634
关键词：
Acetates Acute Agonist American Anatomy Animals Antigens Bacteria Butyrates Cell Line Cell physiology Chronic Colon Communication Crohn&apos s disease Development Disease Disease Progression Disease model Energy-Generating Resources Epithelial Epithelial Cells Epithelium Event Formulation Gastrointestinal Diseases Gastrointestinal tract structure Genes Genetic Transcription Goals Health Homeostasis Hypoxia Hypoxia Inducible Factor Immune response In Vitro Individual Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Innate Immune Response Intestinal Diseases Intestinal Mucosa Intestines Mediating Metabolic Metabolic Pathway Metabolism Modeling Molecular Mucositis Mucous Membrane Mus Outcome Oxygen Pathway interactions Pharmacology Physiological Positioning Attribute Propionates Receptor Signaling Regulation Reporting Resolution Role Signal Transduction Submucosa TNF gene Testing Tissues Ulcerative Colitis Volatile Fatty Acids Work Wound Healing base commensal microbes defined contribution design experimental study gut microbiota healing hypoxia inducible factor 1 in vitro Model in vivo in vivo Model inflammatory milieu insight interest interleukin-10 receptor microbial microbial host microbiota new therapeutic target novel public health relevance receptor receptor expression response tool tributyrin

项目摘要

DESCRIPTION (provided by applicant): Mucosal diseases such as Inflammatory Bowel Disease (IBD) result from changes in the microbiota (dysbiosis) in the face of ongoing inflammation. Our ongoing studies have identified a significant role for microbial-derived short chain fatty acids (SCFA) in intestinal disease and an important role for the transcriptional regulator hypoxia-inducible factor (HIF) in protection during intestinal inflammation. It remains unclear exactly how the host and the microbiota communicate and whether such communication is relevant to disease progression or inflammatory resolution. This study is designed to test the hypothesis that host-microbial crosstalk via SCFA promotes mucosal integrity, with HIF as the epithelial messenger and the epithelial IL-10R as the target. Three integrated specific aims are proposed to test this hypothesis. First, we will define the SCFA signaling axis for HIF stabilization using an established intestinal epithelial model in vitro and in vivo. Specifically, e will define how the epithelial SCFA signaling receptor GPR109a and impacts HIF stabilization in the mucosa and how such signaling promotes mucosal integrity. Second, we will elucidate the contribution of SCFA-induced HIF on epithelial IL-10R expression and signaling. Third, we will determine the relevance of this SCFA-HIF-IL-10R axis in mucosal inflammatory models. The overall aim of this proposal is to elucidate the host-microbial communication events mediating mucosal epithelial responses to inflammation.

描述（由申请人提供）：粘液性疾病，如炎症性肠病（IBD），是由于面临持续炎症时微生物群的变化（生态失调）引起的。我们正在进行的研究已经确定了微生物来源的短链脂肪酸（SCFA）在肠道疾病中的重要作用，以及转录调节因子缺氧诱导因子（HIF）在肠道炎症保护中的重要作用。目前尚不清楚宿主和微生物群是如何交流的，以及这种交流是否与疾病进展或炎症消退有关。本研究旨在验证以下假设：通过SCFA的宿主-微生物串扰促进粘膜完整性，HIF作为上皮信使，上皮IL-10 R作为靶标。提出了三个综合的具体目标来检验这一假设。首先，我们将使用已建立的肠上皮细胞模型在体外和体内定义用于HIF稳定的SCFA信号传导轴。具体而言，e将定义上皮SCFA信号传导受体GPR 109 a如何影响粘膜中的HIF稳定性以及这种信号传导如何促进粘膜完整性。其次，我们将阐明SCFA诱导的HIF对上皮细胞IL-10 R表达和信号传导的贡献。第三，我们将确定该SCFA-HIF-IL-10 R轴在粘膜炎症模型中的相关性。本提案的总体目标是阐明介导粘膜上皮炎症反应的宿主-微生物通讯事件。