Immunologic Dysfunction in Biliary Atresia

胆道闭锁的免疫功能障碍

基本信息

批准号：
8600672
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 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8600672
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 Hepatic Human IL4R gene IL8 gene Immune Immune system Immunologics In Vitro Individual Inflammatory Inflammatory Response Injury Interferons 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 TNF gene Testing Time Tissues United States Virus 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 public health relevance 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 TNF? 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-IL4R?-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，也是小儿肝移植的首要适应症。它是由肝外胆管炎症和纤维化阻塞引起的，表现为新生儿黄疸。尽管得到及时诊断和手术治疗，但疾病仍在进展并导致大量发病率和死亡率。尽管病因学在很大程度上仍未明确，但追求该奖项先前目标的研究对疾病的致病机制有了深入的了解。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。与疾病的多因素基础相一致，我们还发现在实验和人体组织中胆道损伤期间发生 Th2 信号激活。综合起来，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点。在这个竞争性的更新应用中，我们提出了一个统一的假设，即肝脏炎症细胞具有双重作用，既作为胆管损伤的效应器，又作为恢复上皮完整性的生存信号的提供者。该假设将在三个密切相关但独立的目标中得到检验。在目标 1 中，我们将定义淋巴细胞可溶性配体诱导上皮损伤的机制。这将通过应用体外强大的动物模型系统来检查 TNF 如何完成？信号传导和颗粒酶充当胆管细胞裂解的分子执行者。在目标 2 中，我们将确定巨噬细胞和中性粒细胞作为胆道损伤促进者的作用。这一目标建立在初步实验的基础上，该实验表明新生儿 Livr 表达巨噬细胞和中性粒细胞化学引诱物。因此，我们将使用基因工程小鼠来探索个体细胞类型在调节产生疾病表型的炎症反应中的作用。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。我们得出的初步证据表明，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。在这里，我们建议通过研究实验性胆道闭锁中胆管细胞增殖和上皮完整性恢复中警报素 IL33 和 IL13-IL4R?-STAT6 轴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。这些结果将确定一系列新疗法的靶标，这些新疗法可阻止疾病进展、恢复胆道上皮并促进胆道闭锁患者的长期生存。