Modulation of the biliary immune niche by the microbiome

微生物组对胆道免疫生态位的调节

基本信息

批准号：
10349405
负责人：
CLAIRE E O'LEARY
金额：
$ 16.2万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-20 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10349405
关键词：
Acute Adult Biliary Biliary Atresia Biliary Tract Cancer Biliary Tract Diseases Biology Cell Shape Cells Childhood Cholangiocarcinoma Cholecystitis Cholelithiasis Cholesterol Chronic Clinical Collaborations Data Dendritic Cells Development Development Plans Diet Disease Disease Progression Environmental Risk Factor Epithelial Cells Epithelium Event Extrahepatic Extrahepatic Bile Ducts Frequencies Gallbladder Germ-Free Health Homeostasis Hospitalization Human Immune Immune system Immunologics Immunology Infiltration Inflammation Inflammatory Inflammatory Response Integration Host Factors Left Ligands Link Liver Liver Failure Lymphocyte Lymphoid Cell Macrophage Malignant Neoplasms Methods Mucous Membrane Mus Neutrophil Infiltration Normal tissue morphology Operative Surgical Procedures Pathologic Pathology Phenotype Play Population Process Property Recording of previous events Reproducibility Research Resolution Risk Risk Factors Role Secretory Cell Sensory Severities Severity of illness Shapes Signal Transduction Stromal Cells Surface Testing Therapeutic Intervention Tissue atlas Tissues Training Volatile Fatty Acids Work biliary tract career development cell type design gallstone disease granulocyte host microbiome immune cell infiltrate immunoregulation liver transplantation microbial microbiome microbiota mortality neutrophil post-doctoral training primary sclerosing cholangitis receptor repository single cell sequencing single-cell RNA sequencing therapeutic target

项目摘要

PROJECT SUMMARY/ABSTRACT Biliary tract disease and inflammation, including pediatric biliary atresia and primary sclerosing cholangitis, are leading causes of liver failure. Chronic biliary inflammation, which can be associated with the presence of gallstones, is a risk factor for development of cholangiocarcinoma, a rare but deadly malignancy. Acute inflammation of the gallbladder, or cholecystitis, accounts for 20% of all biliary tract disease hospitalizations, usually requires surgical intervention and has significant mortality if left untreated. Together, biliary tract disease, including common gallstones, represents an enormous human health burden. Biliary tract inflammation plays clear roles in progression of various common and rare biliary diseases, however our understanding of inflammation and immune processes within the biliary tract are exceedingly limited. The resident immune cell populations in the extrahepatic biliary tree at homeostasis have never been characterized, and whether host or environmental factors can influence the development of the biliary niche has never been explored. It is unknown if resident biliary immune cells could impact development and progression of biliary disease. During my postdoctoral training, I developed a reproducible tissue digest method that yields highly viable immune, epithelial, and stromal cell populations. Single cell RNA sequencing revealed that there is a diversity of resident immune cells present at homeostasis in the mouse gallbladder/extrahepatic bile ducts, including innate lymphoid cells, adaptive lymphocytes, neutrophils, macrophages, and dendritic cells. In the course of studying biliary tuft cells—rare, chemosensory epithelial cells with known immunomodulating properties—I found that the biliary immune niche is altered in the absence of tuft cells, and is also sensitive to the microbiome-status of the host. My data suggest that the microbiome and biliary epithelial cells (including tuft cells) regulate the establishment of the biliary immune niche. In this proposal, I will test the role of the microbiome and microbial metabolites in setting biliary immune “tone,” and will define a role for tuft cells in regulating the biliary immune cell make-up. I will test whether alterations in the biliary immune niche at homeostasis, specifically the presence or absence of neutrophils, can impact the progression of cholesterol gallstone disease. To accomplish these aims, I have formed collaborations with experts in liver/biliary biology and microbiome manipulations, and have established a career development plan that will facilitate increasing computational independence. These studies will reveal new links between host factors and biliary inflammation, with the potential for therapeutic targeting of biliary epithelial cells and the microbiome to impact biliary health and disease.

项目摘要/摘要胆道疾病和感染，包括小儿胆道闭锁和原发性硬化性胆管炎肝衰竭的主要原因。慢性胆道炎症，可能与存在有关胆结石是胆管癌发展的危险因素，这是一种罕见但致命的恶性肿瘤。急性胆囊炎或胆囊炎的炎症占所有胆道疾病住院的20％通常需要手术干预，如果未治疗，则具有明显的死亡率。在一起，胆道疾病，包括常见的胆结石，代表着巨大的人类健康伯恩。胆道炎症在各种常见和稀有胆道疾病的进展中明确的作用，但是我们对胆道内部的炎症和免疫过程受到极大限制。稳态的居民种群的居民免疫细胞种群从未有过表征，宿主还是环境因素是否可以影响胆道利基的发展从未探索过。尚不清楚居民胆道免疫细胞是否会影响发育和进展胆道疾病。在博士后培训期间，我开发了一种可再现的组织摘要方法，该方法产生高度可行的免疫，上皮和基质细胞群体。单细胞RNA测序表明有在小鼠胆囊/外pa骨外胆管中，有许多居民的免疫力，包括先天淋巴样细胞，适应性淋巴细胞，中性粒细胞，巨噬细胞和树突状细胞。研究胆道簇细胞的过程 - 具有已知免疫调节的化学感应上皮细胞性质 - 我发现，在没有簇细胞的情况下，胆道免疫小众发生了变化，并且对宿主的微生物组态。我的数据表明微生物组和胆道上皮细胞（包括簇细胞）调节胆汁免疫利基的建立。在此提案中，我将测试微生物组的作用和微生物代谢物在设置胆道免疫“张力”中，并将定义簇细胞调节的作用胆道免疫细胞构成。我将测试是否在体内稳定性的胆道免疫利基市场中发生了变化，特别是中性粒细胞的存在或不存在会影响胆固醇胆结石疾病的进展。到完成这些目标，我与肝脏/胆道生物学和微生物组的专家建立了合作操纵，并制定了职业发展计划，该计划将有助于增加计算独立。这些研究将揭示宿主因素与胆道炎症之间的新联系，与胆道上皮细胞和微生物组的治疗靶向潜力，以影响胆道健康和疾病。