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Development and Function of Biliary Tuft Cells

胆管簇细胞的发育和功能

基本信息

批准号：
10543652
负责人：
CLAIRE E O'LEARY
金额：
$ 0.25万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543652
关键词：
Acute Address Adult Agonist Anatomy Back Bacterial Infections Bile Acids Bile fluid Biliary Biliary Tract Diseases Cell Compartmentation Cell Death Cell physiology Cells Complex Data Detection Development Discrimination Disease Disease Progression Distal part of ileum Duct (organ) structure Epithelial Epithelial Cells Excretory function Exhibits Exposure to Extrahepatic Extrahepatic Bile Ducts Failure Flow Cytometry Functional disorder Future Gallbladder Gene Expression Profile Genes Health Hepatobiliary Heterogeneity Homeostasis Human Immune Immune response Immune system Immunity In Vitro Infection Infiltration Inflammation Inflammatory Inflammatory Response Injury Interleukin-13 Interleukins Intestines Investigation Knowledge Lead Link Liver Location Lymphoid Cell Maintenance Mechanical Stress Modeling Mouse Strains Mus Neonatal Neutrophil Infiltration Obstruction Oral Organoids Pathogenicity Pathologic Pathology Physiological Play Population Positioning Attribute Process Production Property Regulation Regulatory Pathway Reporter Role Salmonella typhimurium Secretory Cell Sensory Shapes Signal Transduction Small Intestines Solubility Stimulus Stromal Cells System Testing Therapeutic Tissues Transcript Tumor-infiltrating immune cells Up-Regulation Work Xenobiotics base biliary tract clinically relevant cytokine genetic signature high resolution imaging immune activation immune function immunoregulation in vivo insight intestinal epithelium liver injury mouse model neutrophil new therapeutic target novel pathogen prevent programs recruit response single cell sequencing stem cells tool

项目摘要

PROJECT SUMMARY The biliary system stores, modifies, and provides regulated excretion of bile, necessitating exposure to potentially damaging, highly acidic luminal contents. Maintenance of a robust epithelial barrier, limited immune responses to normal bile perturbations, and discrimination between pathogenic and non-pathogenic changes in luminal contents are critical to homeostatic biliary function. Barrier failure or aberrant immune regulation can lead to inflammation, a key component of disease progression in biliary diseases known as cholangiopathies. Despite the critical role biliary quiescence plays in function of the hepatobiliary system, our understanding of homeostatic immune regulation in the biliary tree is limited. One clue may be the striking abundance of tuft cells in the biliary epithelium. Tuft cells, secretory epithelial cells with chemosensory machinery, nucleate an immune cell “circuit” in the small intestine in which tuft cell IL-25 promotes the production of IL-13 from innate lymphoid cells. Whether similar immune or tissue-modulating roles for tuft cells exist in other tissues is only now being explored. We have found that biliary tuft cells express the core tuft cell gene program, a tissue-specific gene signature, and are sensitive to perturbations in bile acid production. Analysis of gallbladder and extrahepatic ducts from tuft cell deficient mice indicates aberrant immune cell accumulation in this tissue in the absence of tuft cells. The known roles of tuft cells in the small intestine suggests that biliary tuft cells could serve to integrate the biliary epithelium with the immune system; in contrast to the small intestine, our data indicate biliary tuft cells could inhibit inflammatory responses. Together, this suggests that biliary tuft cells could play unappreciated roles in bile acid sensing or the adaptive response to perturbed bile acid abundance, and may regulate biliary immune responses. This proposal will test the hypothesis that biliary tuft cell abundance is controlled by bile content, and that tuft cells repress biliary immune responses at homeostasis. We will take advantage of sensitive, IL-25 based in vivo tools to characterize the abundance, position, and developmental regulation of tuft cells throughout the biliary tree. We will seek to understand the mechanism whereby bile acid manipulation impacts biliary tuft cell abundance using in vitro and in vivo approaches. We will assess how tuft cells might regulate the immune “tone” of the biliary tree, and what consequences this may have during infection. The secretory and chemosensory functions attributed to tuft cells make these cells attractive integrators of bile content with tissue or immune cell responses, while the unique gene expression profile of biliary tuft cells suggests therapeutic malleability. In addition to the potential for defining novel, tissue-specific roles for biliary tuft cells, our work will add to the existing knowledge on biliary immune responses, as well as the understanding of heterogeneity among biliary epithelial, stromal, and immune cells. Future studies will investigate tuft cell function in more complex models of hepatobiliary inflammation and disease and explore the correlation of tuft cell abundance with human biliary disease states, with great potential to advance new therapeutic targets in biliary pathologies.

项目总结