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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：
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
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/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

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.

项目总结