Immunologic Dysfunction in Biliary Atresia

胆道闭锁的免疫功能障碍

基本信息

批准号：
8825487
负责人：
JORGE A. BEZERRA
金额：
$ 40.79万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8825487
关键词：
Address Animal Model Apoptosis Award Bile fluid Biliary Biliary Atresia Biological Biological Models CD8-Positive T-Lymphocytes Cells Chemotactic Factors Child Child health care Childhood Cholestasis Cirrhosis Cytolysis Data Analyses Dendritic Cells Diagnosis Disease Disease Progression Duct (organ) structure Effector Cell Epithelial Epithelium Etiology Extrahepatic Cholestasis Fibrosis Fostering Functional disorder Genetically Engineered Mouse Goals Granzyme Health Hepatic Human IL8 gene Immune Immune system Immunologics In Vitro Individual Inflammatory Inflammatory Response Injury Interferon Type II Interleukin-13 Interleukin-15 Knowledge Ligands Liver Liver diseases Lymphocyte Medical Mitogens Modeling Molecular Molecular Profiling Morbidity - disease rate Mucous Membrane Mus Myeloid Cells Natural Killer Cells Nature Neonatal Neonatal Jaundice Neutrophil Infiltration Newborn Infant Obstruction Operative Surgical Procedures Outcome Pathogenesis Pathway interactions Patients Process Property Reporting Role STAT6 gene Signal Transduction Source Staging Subgroup Testing Time Tissues Tumor Necrosis Factor-alpha United States Virus Diseases Work base bile duct cell type cholangiocyte chronic liver disease cytokine cytotoxic disease phenotype follow-up human tissue improved injured liver inflammation liver transplantation macrophage mortality neutrophil new growth new therapeutic target novel prevent promoter repaired research study restoration therapeutic target tissue repair

项目摘要

DESCRIPTION (provided by applicant): Biliary atresia is the most common cause of end-stage cirrhosis in children and the number one indication for pediatric liver transplantation. It results from an inflammatory and fibrosing obstruction of extrahepatic bile ducts that presents as neonatal jaundice. Despite prompt diagnosis and surgical treatment, the disease progresses and causes substantial morbidity and mortality. Although the etiology remains largely undefined, studies pursuing the previous aims of this award have advanced knowledge of pathogenic mechanisms of disease. Specifically, we uncovered a sequential activation of dendritic, NK and CD8+ cells that disrupts the bile duct mucosa and promotes lumenal obstruction. Consistent with a multifactorial basis of disease, we also found that the activation of Th2 signals occurs during biliary injury experimentally and in human tissues. Combined, these studies placed the immune system in a central point of pathogenesis and began to identify potential therapeutic targets. In this competing renewal application, we propose a unifying hypothesis that hepatic inflammatory cells have a dual role as effectors of bile duct injury and as suppliers of survival signals to restore epithelial integrity. This hypothesis will be tested in three closely related bu independent aims. In Aim 1, we will define the mechanisms used by lymphocyte soluble ligands to induce epithelial injury. This will be done by applying in vitro and powerful animal model systems to examine how TNFα signaling and granzymes serve as molecular executors of cholangiocyte lysis. In Aim 2, we will determine the roles of macrophages and neutrophils as promoters of biliary injury. This aim is built on initial experiments showing that the neonatal livr expresses macrophage and neutrophil chemoattractants. Thus, we will use genetically engineered mice to explore the role of individual cell types in modulating the inflammatory response that produces the disease phenotype. And in Aim 3, we will investigate Th2 cytokines as survival signals to restore epithelial integrity. We generated preliminary evidence that liver-based myeloid cells produce Th2 survival signals with potent mitogenic properties to cholangiocytes. Here, we propose to dissect these signals by investigating the properties of the alarmin IL33 and the IL13-IL4Rα-STAT6 axis in cholangiocyte proliferation and restoration of epithelial integrity in experimental biliary atresia. Upon completion, the proposed experiments will advance our understanding of the pathogenic mechanisms of disease and uncover new growth signals that promote repair of the injured tissue. These results will identify an array of targets for new therapies that block progression of disease, restore the biliary epithelium, and foster long-term survival of patients with biliary atresia.

描述（由申请人提供）：胆道闭锁是儿童终末期肝硬化的最常见原因，也是儿童肝移植的首要适应症。尽管如此，它是由肝外胆管炎症和纤维化阻塞引起的。尽管病因尚未明确，但追求该奖项先前目标的研究已经取得了先进的知识。具体来说，我们发现树突状细胞、NK 细胞和 CD8+ 细胞的连续激活会破坏胆管粘膜并促进管腔阻塞，这与疾病的多因素基础一致，我们还发现 Th2 信号的激活发生在结合实验和人体组织中的胆道损伤，这些研究将免疫系统置于发病机制的中心点，并开始确定潜在的治疗靶标。假设肝脏炎症细胞具有作为胆管损伤的效应器和恢复上皮完整性的生存信号提供者的双重作用，该假设将在三个密切相关的独立目标中进行测试，我们将定义所使用的机制。淋巴细胞可溶性配体诱导上皮损伤，这将通过应用体外和强大的动物模型系统来检查 TNFα 信号传导和颗粒酶如何作为胆管细胞裂解的分子执行者来完成。 2，我们将确定巨噬细胞和中性粒细胞作为胆道损伤促进剂的作用，这一目标是建立在表明新生儿livr表达巨噬细胞和中性粒细胞化学引诱剂的基础上的，因此，我们将使用基因工程小鼠来探索单个细胞的作用。在目标 3 中，我们将研究 Th2 细胞因子作为恢复上皮完整性的生存信号。基于肝脏的骨髓细胞产生对胆管细胞具有有效促有丝分裂特性的 Th2 存活信号，在此，我们建议通过研究实验中警报蛋白 IL33 和 IL13-IL4Rα-STAT6 轴在胆管细胞增殖和上皮完整性恢复中的特性来剖析这些信号。完成后，拟议的实验将增进我们对疾病致病机制的理解，并揭示促进受损组织修复的新生长信号。阻止疾病进展、恢复胆道上皮并促进胆道闭锁患者长期生存的新疗法的目标。