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Lymphothrombosis in gut health and disease

肠道健康和疾病中的淋巴血栓形成

基本信息

批准号：
10649640
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
项目类别：
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/10649640
关键词：
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 Fibrinolytic Agents 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 Movement Mucins Mucous Membrane Mus Names PAR-1 Receptor Pathologic Phenotype Physiological Play Predisposition Process Proteins Regulation Reporting Role Salmonella Salmonella infections Signal Transduction Site Small Intestines Source Stimulant Surface Surveys Testing Thrombin Thrombomodulin Thromboplastin Thrombosis Thrombus Tissues Transgenic Mice Vascular System Villus Virulence Yersinia absorption 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

项目摘要

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.

项目概要与其他地方的淋巴管不同，胃肠道中的淋巴系统运输吸收的脂质，并使对肠道微生物组中数十亿细菌的免疫监视。这种专门的功能被认为需要独特的遗传和分子特征，但很少有这样的专门特征被发现。我们的初步研究使用新的 PAR1-Tango 转基因小鼠品系来证明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- 肠道中特有的血栓形成蛋白血栓调节蛋白 (THBD) 和内皮蛋白 C 受体 (EPCR) 淋巴内皮细胞（LEC）。在诱导性、全局 LEC 删除 THBD 或 EPCR 后，我们观察到纤维蛋白血栓形成，特别是在胃肠道淋巴管中，这与肠道淋巴流量减少有关，通过抗生素治疗减少肠道细菌来逆转表型。我们还检测到纤维蛋白血栓的形成野生型动物被肠道细菌病原体沙门氏菌感染后的肠道淋巴管或耶尔森氏菌。这些研究确定了一种新的体内凝血机制，即淋巴血栓形成，它对肠道淋巴管必须受到肠道 LEC 的调节才能维持正常的肠道淋巴功能。这该提案的目标将使用新颖的分子和遗传工具来（i）充分定义肠道淋巴脉管系统中的淋巴血栓形成，(ii) 测试胃肠道淋巴血栓形成是否以及如何与肠道微生物群，以及（iii）确定肠道淋巴血栓形成在胃肠道感染期间的作用。我们预测这些研究将揭示血管系统外血栓形成的新机制，该机制发挥独特的作用肠道淋巴管在健康和疾病中发挥着重要的功能作用。