Immunologic Dysfunction in Biliary Atresia

胆道闭锁的免疫功能障碍

基本信息

批准号：
7572979
负责人：
JORGE A. BEZERRA
金额：
$ 31.88万
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：
2003
资助国家：
美国
起止时间：
2003-08-15 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7572979
关键词：
Apoptosis Award Biliary Biliary Atresia Binding Biological Biological Models Biological Process CD8-Positive T-Lymphocytes CD8B1 gene Cell-Mediated Cytolysis Chemotaxis Child Child health care Childhood Cholangitis Cholestasis Chronic Cirrhosis Complex Data Diagnosis Disease Disease Progression Duct (organ) structure Ductal Epithelium Epithelial Etiology Experimental Models Extrahepatic Extrahepatic Bile Ducts Extrahepatic Cholestasis Fibrosis Functional disorder Funding Future Gene Expression Profile Goals Hepatic Immune response Immune system Immunologics Individual Infant Inflammatory Injury Interferon Type II Interferons Interleukin-12 Laboratories Life Ligands Liver Liver diseases Mediator of activation protein Medical Modeling Molecular Molecular Profiling Mus Natural Killer Cells Nature Neonatal Obstruction Operative Surgical Procedures Outcome Pathogenesis Peptide Hydrolases Perinatal Phase Phenotype Process Property Research Role Rotavirus Signal Transduction Staging T-Lymphocyte TNF gene Testing Time Tumor Necrosis Factor-alpha United States Viral Work base bile duct cell injury cell type cellular targeting cholangiocyte cytokine cytotoxic cytotoxicity improved in vivo injured liver transplantation macrophage mouse model neutrophil new therapeutic target novel postnatal prevent programs research study response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Biliary atresia results from an inflammatory and fibrosing obstruction of extrahepatic bile ducts in young infants. Despite prompt diagnosis and surgical treatment, the disease progresses and leads to end-stage cirrhosis in most infants. The etiology and pathogenic mechanisms of disease are largely undefined. In the first period of this award, we searched for prominent molecular processes in livers of infants with biliary atresia and found a dominant interferon-gamma (IFN?)-rich proinflammatory circuit at the time of diagnosis. We then used a novel mouse model of experimental atresia to directly examine the role of IFN? in regulating the biliary atresia phenotype. This model displayed a similar proinflammatory process in the liver. Most notably, the in vivo loss of IFN?, completely prevented duct obstruction and improved long-term outcome. In this competing renewal application, we propose an overriding hypothesis that the pathogenic mechanisms of biliary atresia begin with an epithelial injury by the innate immune system and progress to duct obstruction by the activation of an exuberant adaptive immune response. This hypothesis will be tested in three closely related but independent aims. In Aim 1, we will determine the role of hepatic CD8+ T cells in neonatal injury of bile ducts. This will be done by investigating how CD8+ T cells engage cholangiocytes through recognition and binding to the MHC-I complex, and by dissecting the intracellular signals trigged by IFN? to render cholangiocytes susceptible to apoptosis induced by tumor necrosis factor-alpha. In Aim 2, we will establish the mechanisms by which hepatic NK cells injure the neonatal duct epithelium. Using a similar experimental approach, we will examine the mechanisms of NK cell-mediated cytotoxicity and how NK cells work in synergy with CD8+ T cells to induce epithelial injury and duct obstruction. And in Aim 3, we will define how hepatic macrophages trigger the innate immune response following a neonatal viral challenge that targets the bile ducts. In this aim, we will determine whether hepatic macrophages are targeted by rotavirus. In related experiments, we will also investigate the molecular mechanisms by which infected macrophages induce chemotaxis to neutrophils and, possibly, cytotoxicity to cholangiocytes. Upon completion, the proposed experiments will advance our understanding of the biological basis for experimental atresia and potentially identify new therapeutic targets to stop progression of disease and improve long-term outcome in children with biliary atresia. Project Narrative: This project studies biliary atresia, the most common cause of chronic liver disease in children and the leading indicator for pediatric liver transplantation in the United States. With the aim to determine key cellular and molecular mechanisms of disease pathogenesis, the proposed experiments will use a unique mouse model of neonatal biliary injury to dissect the biological processes regulating the injury and obstruction of extrahepatic bile ducts.

描述（由申请人提供）：胆道闭锁是由于年轻婴儿肝外胆管的炎症和纤维性阻塞引起的。尽管迅速诊断和手术治疗，但该疾病仍在进展并导致大多数婴儿的终末期。疾病的病因和致病机制在很大程度上是不确定的。在该奖项的第一阶段，我们在患有胆道闭锁的婴儿的肝脏中搜索了突出的分子过程，并发现诊断时占主导地位的干扰素 - γ-富含促炎的促炎性回路。然后，我们使用一种新型的实验性闭锁的小鼠模型来直接检查IFN的作用？在调节胆道闭锁表型中。该模型在肝脏中显示出类似的促炎过程。最值得注意的是，IFN的体内损失完全阻止了管道阻塞并改善了长期结局。在这种相互竞争的更新应用中，我们提出了一个推翻假设，即胆道闭锁的致病机制始于先天免疫系统的上皮损伤，并通过激活繁殖的适应性免疫反应而进步导致导管阻塞。该假设将以三个密切相关但独立的目的进行检验。在AIM 1中，我们将确定肝CD8+ T细胞在胆管新生儿损伤中的作用。这将通过研究CD8+ T细胞如何通过识别和与MHC-I复合物结合以及解剖IFN触发的细胞内信号来进行胆管细胞？为了使胆管细胞易受肿瘤坏死因子-Alpha诱导的凋亡。在AIM 2中，我们将建立肝NK细胞损害新生儿管道上皮的机制。使用类似的实验方法，我们将检查NK细胞介导的细胞毒性的机制，以及NK细胞如何与CD8+ T细胞协同作用，以诱导上皮损伤和导管阻塞。在AIM 3中，我们将定义肝巨噬细胞在针对胆管的新生儿病毒挑战之后如何触发先天免疫反应。在此目标中，我们将确定肝巨噬细胞是否是轮状病毒的靶向。在相关的实验中，我们还将研究分子机制，通过这些机制，感染巨噬细胞会诱导中性粒细胞趋化性，并可能将细胞毒性对胆管细胞诱导。完成后，拟议的实验将提高我们对实验性闭锁生物学基础的理解，并有可能确定新的治疗靶标，以阻止疾病进展并改善胆道闭锁儿童的长期结局。项目叙述：该项目研究胆道闭锁，这是儿童慢性肝病的最常见原因，也是美国小儿肝移植的主要指标。为了确定疾病发病机理的关键细胞和分子机制，提出的实验将使用新生儿胆道损伤的独特小鼠模型来剖析调节肝外胆管损伤和阻塞的生物学过程。