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

 描述(由申请人提供)：黏膜疾病，如炎症性肠病(IBD)，是由于面对持续的炎症时微生物区系(生物失调)的变化造成的。我们正在进行的研究已经确定了微生物衍生的短链脂肪酸(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)在肠道炎症过程中的保护作用。目前尚不清楚宿主和微生物区系到底是如何沟通的，以及这种沟通是否与疾病进展或炎症消退有关。本研究旨在以HIF为上皮信使，以上皮细胞IL-10R为靶点，通过SCFA验证宿主-微生物串扰促进粘膜完整性的假说。本文提出了三个综合的具体目标来检验这一假说。首先，我们将使用已建立的体外和体内肠上皮模型来确定稳定HIF的SCFA信号轴。具体地说，e将定义上皮性SCFA信号受体Gpr109a如何影响粘膜中的HIF稳定性，以及这种信号如何促进粘膜的完整性。其次，我们将阐明SCFA诱导的HIF在上皮细胞IL-10R表达和信号转导中的作用。第三，我们将确定这个SCFA-HIF-IL-10R轴在粘膜炎症模型中的相关性。这一建议的总体目标是阐明介导黏膜上皮细胞对炎症反应的宿主-微生物通讯事件。

 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.