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（由应用提供）：胆道闭锁是儿童终末期肝硬化的最常见原因，也是小儿肝移植的第一指示。它是由炎症性和触觉的对象化呈炎症性和纤维化的对象化，呈现为新生儿珍妮德（Janide）。尽管及时诊断和手术治疗，该疾病仍在进展并引起大量的发病率和死亡率。尽管病因仍然在很大程度上不确定，但追求该奖项的先前目标的研究具有对疾病致病机制的高级知识。具体而言，我们发现了破坏胆管粘膜的树突状，NK和CD8+细胞的顺序激活，并促进了液体客观化。与疾病的多因素基础一致，我们还发现Th2信号的激活发生在实验和人体组织中。这些研究结合在一起，将免疫系统置于发病机理的中心点，并开始鉴定潜在的治疗靶标。在这种竞争性的更新应用中，我们提出了一个统一的假设，即肝炎性细胞具有双重作用，作为胆管损伤的影响以及作为恢复上皮完整性的生存信号的供应商。该假设将在三个密切相关的BU独立目标中进行检验。在AIM 1中，我们将定义淋巴细胞固体配体诱导上皮损伤的机制。这将通过应用体外和功能强大的动物模型系统来研究TNFα信号传导和颗粒酶如何用作胆管细胞裂解的分子执行者。在AIM 2中，我们将确定巨噬细胞和中性粒细胞作为胆道损伤的启动子的作用。该目标建立在初始实验的基础上，表明新生儿LIVR表达巨噬细胞和中性粒细胞化学吸引剂。这是，我们将使用一般的工程小鼠来探索单个细胞类型在调节产生疾病表型的炎症反应中的作用。在AIM 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。我们产生了初步证据，表明肝脏基髓样细胞产生具有潜在有丝分裂特性的Th2存活信号。在这里，我们建议通过研究胆管细胞增殖中的Alarmin IL33和IL13-IL33和IL13-IL33和IL13-IL4Rα-STAT6轴的特性来剖析这些信号。完成后，提出的实验将提高我们对疾病的致病机制的理解，并发现促进受伤组织修复的新生长信号。这些结果将确定针对新疗法的一系列靶标，以阻止疾病进展，恢复胆道上皮并促进胆道闭锁患者的长期生存。