Immunologic Dysfunction in Biliary Atresia

胆道闭锁的免疫功能障碍

• 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
• 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

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，也是小儿肝移植的第一指示。它是由于肝外胆管的炎症和纤维纤维障碍物的障碍物，其呈现为新生儿黄疸。尽管迅速诊断和手术治疗，该疾病仍在进展并导致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，我们发现了树突状，NK和CD8+细胞的顺序激活，该细胞破坏了胆管粘膜并促进了腔内障碍物。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，即肝炎症细胞作为胆管损伤的效应子和作为恢复上皮完整性的生存信号的供应商的双重作用。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可溶性配体诱导上皮损伤的机制。这将通过应用体外和强大的动物模型系统来检查TNF的方式来完成？信号传导和颗粒酶是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。因此，我们将使用基因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，表明肝脏基细胞产生具有有效的有丝分裂特性的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-IL4R？-STAT6轴的特性来剖析这些信号，并在实验性胆道上的胆管细胞增殖和上皮完整性的恢复中恢复。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。