Defining the role of S1p and myeloid cells during enterotoxigenic B. fragilis infection

定义 S1p 和骨髓细胞在产肠毒素脆弱拟杆菌感染过程中的作用

基本信息

批准号：
10369893
负责人：
Zhong-Bin Deng
金额：
$ 23.41万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10369893
关键词：
Acetyl Coenzyme A Acute Diarrhea Anaerobic Bacteria ApcMin/+ mice Bacteroides fragilis Cell Proliferation Cell physiology Cells Cellular Metabolic Process Ceramidase Ceramides Colitis Colon Colorectal Cancer Data Development Diet Dinoprostone Disease Environment Enzymes Epithelial Epithelial Cells Fatty Acids General Population Genes Histone Acetylation Human ITGAM gene Immune Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Innate Immune Response Interleukin-17 Intestines Lead Link Lipids Liver Lymphocyte Function Metabolic Metabolism Modeling Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Nuclear PPAR gamma PTGS2 gene Pathogenesis Pathway interactions Phosphorylation Production Property Proteins Reaction Regulation Role Shapes Signal Transduction Sphingolipids Sphingosine Steroids Testing Therapeutic Toxin Translating blood glucose regulation cell motility colon tumorigenesis dietary sphingolipids extracellular gene induction granulocyte gut bacteria gut dysbiosis histone modification inflammatory disease of the intestine intestinal epithelium lipid metabolism microbial migration monocyte new therapeutic target polarized cell promoter recruit response sphingosine 1-phosphate sphingosine kinase tumorigenesis

项目摘要

Enterotoxigenic Bacteroides fragilis (ETBF) has been associated with acute diarrheal, inflammatory bowel disease, and colorectal cancer (CRC). ETBF oncogenesis requires the coordinated action of its toxin, BFT, and an inflammatory response to orchestrate the recruitment of myeloid cells, but how ETBF recruits colonic myeloid cells remains poorly understood. S1p acts as bioactive sphingolipid messengers, influencing the myeloid cells migration and regulating colonic inflammation. However, whether ETBF integrates sphingolipid metabolites to determine the metabolism of colonic myeloid cells needs to be explored. Recent evidence indicates that remodeling of myeloid cells metabolism is central to the induction of innate immune response. We found ETBF infection alters the activity of sphingosine kinase, which is linked to metabolic remodeling, histone acetylation and PGE2 production in myeloid cells. Two integrated specific aims are proposed to test: Aim 1 will determine how ETBF infection regulates inflammatory myeloid cells accumulation in the colon. Aim 2 will determine if ETBF alteration of acetyl-CoA contributes to metabolic remodeling in myeloid cells via PPARγ activation. Deeper understanding of the proper role of sphingolipids and their enzymes in controlling the intestinal immune properties and in promoting the pathogenesis and progression of colitis will generate new perspectives in the development of “sphingolipid-centered” therapeutic strategies that control the onset and perpetuation of the ETBF-induced gut inflammation.

肠毒素细菌fragilis（ETBF）与急性腹泻有关炎症性肠病和结直肠癌（CRC）。 ETBF肿瘤发生需要其毒素，BFT和炎症反应的协调作用，以协调招聘在髓样细胞中，但是ETBF如何募集结肠髓样细胞的理解仍然很差。 S1P行为作为生物活性鞘脂的使者，会影响髓样细胞的迁移和调节结肠炎症。但是，ETBF是否整合鞘脂代谢物以确定需要探索结肠髓样细胞的代谢。最近的证据表明髓样细胞代谢的重塑对于诱导先天免疫反应的核心。我们发现ETBF感染改变了鞘氨醇激酶的活性，该活性与代谢有关髓样细胞中的重塑，组蛋白乙酰化和PGE2产生。两个集成的特定提出了目的测试：AIM 1将决定ETBF感染如何调节炎症髓样细胞在结肠中积累。 AIM 2将确定ETBF是否改变了乙酰-COA 通过PPARγ激活有助于髓样细胞中的代谢重塑。更深入的理解鞘脂及其酶在控制肠道中的正确作用特性和促进结肠炎的发病机理和进展将产生新的 “以鞘脂为中心”的理论策略发展的观点 ETBF诱导的肠道注射的发作和延续。