BARC: BILLIARY ATRESIA STUDY IN INFANTS AND CHILDREN (BASIC)

BARC：婴儿和儿童胆道闭锁研究（基础）

• 批准号: 8356678
• 负责人: SAUL J. KARPEN
• 金额: $ 2.22万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356678
• 关键词: Address; Affect; Age; Algorithms; Alleles; Apoptosis; Ascites; Autoimmune Process; Biliary Atresia; Body Fluids; Cessation of life; Child; Childhood; Clinical; Clinical Research; Common bile duct structure; Complex; Computational algorithm; Congenital atresia of extrahepatic bile duct; Databases; Development; Disease; Disease Progression; Duodenum; Epitopes; Etiology; Event; Failure; Funding; Gene Frequency; Genes; Genetic; Genetic Materials; Genetic Polymorphism; Grant; Growth; HLA-A gene; Hemorrhage; Hepatic; Hepatitis; Incidence; Infant; Inflammation; Injury; Live Birth; Liver; Liver diseases; Measures; Morbidity - disease rate; Mutation; National Center for Research Resources; Natural History; Nature; Nutritional; Outcome; Pathogenesis; Patients; Phenotype; Principal Investigator; Procedures; Process; Replacement Therapy; Research; Research Infrastructure; Research Personnel; Resolution; Resources; Role; Sampling; Screening procedure; Sentinel; Series; Severities; Severity of illness; Source; Staging; Supplementation; Transplantation; United States; United States National Institutes of Health; bile duct; cost; fibrogenesis; health related quality of life; infancy; liver transplantation; neonate; novel

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. I. HYPOTHESIS Hypothesis 1: A genetic defect is a likely causative factor for biliary atresia (BA) among children with BA and multiple congenital anomalies. Hypothesis 2: Autoimmune factors are likely to contribute to disease progression or acquisition and can be identified by correlating HLA among children with BA to healthy controls and by comparison of those who develop early complications including, variceal bleed, ascites, and growth failure compared to those who do not. Hypothesis 3a: Sentinel events such as variceal bleeding, ascites and growth failure are earlier predictors of death or need for liver transplantation than the pediatric end-stage liver disease score (PELD). Hypothesis 3b: Health related quality of life will be impaired compared to healthy age matched children and relate to severity of illness. Hypothesis 3c: Growth failure as measured by anthropometrics and nutritional supplementation will be predictive of onset of sentinel events (ascites, variceal bleed, death, and transplant) in the following 24 months. II. SPECIFIC AIMS Little is known about the factors that cause biliary atresia nor the factors that influence disease progression. A variety of genetic, autoimmune and environmental influences have been hypothesized to be important. Most studies to date have focused on the neonate and young child with BA, yet the older surviving child with BA can provide important information about genetics, as well as, natural history. The purpose of this database is to collect the pertinent clinical information, genetic material and body fluid samples to enable investigators to address the above hypotheses and the following related aims: Specific Aim 1. To identify the gene or genes implicated in the etiology of BA Specific Aim 2. To identify polymorphisms that may be important in disease progression such as HLA polymorphisms i.To perform high resolution HLA-A, B, C, DRB1, DRB3 DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1 typing on patients with biliary atresia. ii.To utilize a novel computer algorithm that permits screening large numbers of HLA alleles to detect shared epitopes in patients with biliary atresia. iii.To assess the role of HLA polymorphism in incidence and severity of biliary atresia using traditional analysis of allele frequency and a novel shared epitope algorithm. Specific Aim 3. Characterize the natural history of the older, non-transplanted child with BA. III. BACKGROUND AND SIGNIFICANCE Extrahepatic biliary atresia (BA) is a devastating condition of infancy in which there is obliteration or discontinuity of the hepatic or common bile ducts at any point from the porta hepatitis to the duodenum. When untreated, the condition results in severe liver injury and death in all cases. The development of the hepatoportoenterostomy procedure in 1959 by Kasai has permitted long-term survival in only 20% of the affected infants. The advent of liver replacement therapy has permitted long-term survival in many of the remaining infants, but not without cost and morbidity. The estimated incidence of BA is 1 in 8,000 to 1 in 18,000 live births. Approximately 50 percent of all liver transplantations in children in the United States are for infants with BA-constituting 140-180 liver transplants per year. Despite the devastating nature of this illness and the high cost of its treatment, we still know very little about its pathogenesis nor the factors implicated in disease progression. It is likely that BA is not a single disease, but rather a phenotype of several underlying specific disorders to which the infant liver responds in a stereotypic manner by a complex series of processes, including inflammation, bile duct proliferation, apoptosis and fibrogenesis. Improvement in outcomes will not occur until we have a better understanding of the mechanisms involved in these processes.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 I. 假设 假设1：遗传缺陷是胆道闭锁（BA）和多个先天性异常的儿童中的一个可能的致病因素。 假设二：自身免疫因素可能导致疾病进展或获得，并且可以通过将患有BA的儿童与健康对照组中的HLA相关联，以及通过将那些发生早期并发症的人与那些未发生早期并发症的人进行比较来识别，所述早期并发症包括静脉曲张出血、腹水和生长衰竭。 假设3a：与儿科终末期肝病评分（PELD）相比，静脉曲张出血、腹水和生长障碍等前哨事件是死亡或需要肝移植的早期预测因子。假设3b：与健康年龄匹配的儿童相比，健康相关的生活质量将受损，并与疾病的严重程度相关。假设3c：通过人体测量学和营养补充测量的生长障碍将预测随后24个月内哨兵事件（腹水、静脉曲张出血、死亡和移植）的发生。 二. 具体目标 关于引起胆道闭锁的因素和影响疾病进展的因素知之甚少。各种遗传、自身免疫和环境影响被认为是重要的。迄今为止，大多数研究都集中在新生儿和幼儿与BA，但年龄较大的幸存儿童与BA可以提供有关遗传学的重要信息，以及，自然史。 该数据库的目的是收集相关的临床信息、遗传物质和体液样本，以使研究者能够解决上述假设和以下相关目标： 具体目标1.鉴定与BA病因有关的基因 具体目标2。鉴定在疾病进展中可能重要的多态性，如HLA多态性i.对胆道闭锁患者进行高分辨率HLA-A、B、C、DRB 1、DRB 3、DRB 4、DRB 5、DQA 1、DQB 1、DPA 1和DPB 1分型。利用一种新的计算机算法，可以筛选大量的HLA等位基因，以检测胆道闭锁患者的共同表位。iii.使用传统的等位基因频率分析和新型共享表位算法评估HLA多态性在胆道闭锁发生率和严重程度中的作用。 具体目标3。描述年龄较大的非移植BA患儿的自然病史。 三. 背景和意义 肝外胆道闭锁（BA）是婴儿期的一种毁灭性疾病，其中从肝门到十二指肠的任何一点都存在肝或胆总管闭塞或不连续。 如果不治疗，这种情况在所有情况下都会导致严重的肝损伤和死亡。 加塞于1959年开发的肝门肠吻合术仅允许20%的受影响婴儿长期存活。 肝脏替代疗法的出现使许多剩余的婴儿得以长期生存，但并非没有成本和发病率。 BA的估计发病率为1/8，000至1/18，000活产。 在美国，大约50%的儿童肝移植是针对患有BA的婴儿，每年有140 - 180例肝移植。 尽管这种疾病的破坏性及其治疗费用高昂，但我们对其发病机制和疾病进展的相关因素仍然知之甚少。 很可能BA不是一种单一疾病，而是几种潜在的特定疾病的表型，婴儿肝脏通过一系列复杂的过程（包括炎症、胆管增殖、凋亡和纤维化）以刻板的方式对其作出反应。 在我们更好地理解这些过程所涉及的机制之前，结果不会得到改善。