Lymphothrombosis in gut health and disease

肠道健康和疾病中的淋巴血栓形成

• 批准号: 10200805
• 负责人: IGOR E BRODSKY
• 金额: $ 40.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200805
• 关键词: ARNT gene; Animals; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Infections; Biology; Blood; Cell Maintenance; Cells; Characteristics; Clinical; Coagulation Process; Data; Disease; Disease model; Endothelium; Epithelial Cells; Equilibrium; Exposure to; F2R gene; Fibrin; Gastrointestinal tract structure; Gene Expression; Generations; Genes; Genetic; Genetic Models; Health; Home; Homeostasis; Hour; Human; Immune; Immune response; Immunologic Surveillance; Infection; Inflammatory Bowel Diseases; Intestines; Invaded; Large Intestine; Leukocytes; Link; Lipids; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic function; Modeling; Molecular; Molecular Genetics; Movement; Mucins; Mucous Membrane; Mus; Names; PAR-1 Receptor; Pathologic; Pharmaceutical Preparations; Phenotype; Physiological; Play; Process; Proteins; Regulation; Reporting; Role; Salmonella; Salmonella infections; Signal Transduction; Site; Small Intestines; Source; Surface; Surveys; Testing; Thrombin; Thrombomodulin; Thromboplastin; Thrombosis; Thrombus; Tissues; Transgenic Mice; Vascular System; Villus; Virulence; Yersinia; activated protein C receptor; commensal bacteria; enteric infection; experience; gastrointestinal epithelium; germ free condition; gut bacteria; gut health; gut microbiome; gut microbiota; in vivo; infection risk; lymph flow; lymphatic circulation; lymphatic vasculature; lymphatic vessel; mature animal; microbiome; mouse genetics; novel; pathogen; pathogenic bacteria; pathogenic microbe; prevent; response; secondary lymphoid organ; thrombotic; tool; virtual

Project Summary Unlike lymphatics elsewhere, the lymphatic system in the GI tract transports absorbed lipids and enables immune surveillance of the billions of bacteria in the gut microbiome. Such specialized functions are thought to require unique genetic and molecular characteristics, but few such specialized features have been identified. Our preliminary studies use a new line of PAR1-Tango transgenic mice to demonstrate high thrombin activity specifically in the lymphatic vessels of the gut, a finding consistent with high expression of the endothelial anti- thrombotic proteins thrombomodulin (THBD) and endothelial protein C receptor (EPCR) specifically in gut lymphatic endothelial cells (LECs). Following inducible, global LEC deletion of THBD or EPCR, we observe fibrin thrombus formation specifically in GI lymphatics that is associated with reduced lymph flow from the gut, phenotypes reversed by antibiotic treatment to reduce gut bacteria. We also detect fibrin thrombus formation in the gut lymphatics of wild-type animals following infection by the enteric bacterial pathogens Salmonella or Yersinia. These studies identify a new in vivo clotting mechanism, lymphothrombosis, that is highly specific for gut lymphatic vessels and that must be regulated by gut LECs to maintain normal gut lymphatic function. The aims of this proposal will use novel molecular and genetic tools to (i) fully define the process of lymphothrombosis in the gut lymphatic vasculature, (ii) test whether and how GI lymphothrombosis is linked to gut microbiota, and (iii) determine the role of gut lymphothrombosis during GI infection. We predict that these studies will reveal a novel mechanism of thrombosis outside of the blood vascular system that plays a unique and functionally important role in gut lymphatics in both health and disease.

项目摘要 与其他地方的淋巴管不同，胃肠道的淋巴系统运输吸收的脂类并使 对肠道微生物群中的数十亿细菌进行免疫监测。这种特殊的功能被认为是 需要独特的遗传和分子特征，但很少有这样的专门特征被确定。 我们的初步研究使用了一种新的PAR1-Tango转基因小鼠来展示高凝血酶活性 特别是在肠道的淋巴管中，这一发现与内皮抗-2蛋白的高表达一致。 肠道特异的血栓调节蛋白(THBD)和内皮蛋白C受体(EPCR) 淋巴管内皮细胞。在THBD或EPCR的可诱导、全局LEC缺失之后，我们观察到 胃肠道淋巴管中纤维蛋白血栓的形成与肠道淋巴流量减少有关， 通过抗生素治疗逆转表型以减少肠道细菌。我们还检测到纤维蛋白血栓的形成 野生动物感染肠道致病菌沙门氏菌或沙门氏菌后的肠道淋巴管 耶尔西尼亚。这些研究确定了一种新的体内凝血机制，淋巴管血栓症，它对 肠道淋巴管，这必须由肠道LEC调节，以维持正常的肠道淋巴功能。这个 这项提案的目的将使用新的分子和遗传工具来(I)充分定义 肠道淋巴管中的淋巴血栓病，(Ii)测试胃肠道淋巴血栓症是否以及如何与 肠道微生物区系，以及(Iii)确定肠道淋巴血栓形成在胃肠道感染中的作用。我们预测，这些 研究将揭示一种新的血栓形成机制，它在血管系统外发挥着独特的作用 对肠道淋巴管在健康和疾病中都起着重要的作用。