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：
9027837
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/9027837
关键词：
Acetates Acute Agonist American 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 tract structure Genes Goals Healed Health Homeostasis Hypoxia Hypoxia Inducible Factor Immune response In Vitro Individual Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory disease of the intestine Interleukin-10 Intestinal Diseases Intestinal Mucosa Intestines Lead Maps Mediating Metabolic Metabolic Pathway Metabolism Modeling Molecular Mucositis Mucous Membrane Mus Outcome Oxygen Pathway interactions Physiological Positioning Attribute Propionates Receptor Signaling Regulation Reporting Research Design Resolution Role Signal Transduction Submucosa TNF gene Testing Tissues Ulcerative Colitis Volatile Fatty Acids Work Wound Healing base commensal microbes defined contribution design gut microbiota healing hypoxia inducible factor 1 in vitro Model in vivo in vivo Model insight interest microbial microbial host microbiota new therapeutic target novel receptor receptor expression research study 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）：炎症性肠病 (IBD) 等粘膜疾病是由于持续炎症导致微生物群发生变化（菌群失调）所致。我们正在进行的研究已确定微生物衍生的短链脂肪酸具有重要作用。 SCFA）在肠道疾病中的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如何进行沟通和交流。这种通讯是否与疾病进展或炎症消退相关，本研究旨在检验以下假设：以 HIF 为上皮信使，以上皮 IL-10R 为靶标，通过 SCFA 进行宿主微生物串扰可促进粘膜完整性。首先，我们将使用已建立的体外和体内肠上皮模型来定义 HIF 稳定的 SCFA 信号轴。 SCFA 信号受体 GPR109a 并影响粘膜中的 HIF 稳定性，以及这种信号如何促进粘膜完整性。其次，我们将阐明 SCFA 诱导的 HIF 对上皮 IL-10R 表达和信号传导的贡献。第三，我们将确定该 SCFA 的相关性。 -粘膜炎症模型中的 HIF-IL-10R 轴该提案的总体目标是阐明介导宿主-微生物通讯事件。粘膜上皮对炎症的反应。