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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 I.假设 假设1：遗传缺陷可能是BA和多个先天异常的儿童胆道闭锁（BA）的可能因素。 假设2：自身免疫性因素可能有助于疾病的进展或获得，并且可以通过将BA儿童与健康对照儿童之间的HLA与HLA相关，并比较那些与不相比的早期并发症的人，包括静脉曲张，腹水和生长失败。 假设3a：诸如静脉曲张，腹水和生长衰竭之类的前哨事件比儿科终末期肝病评分（PELD）更早地预测了死亡或肝移植的需求。假设3B：与健康年龄相匹配的儿童相比，与健康相关的生活质量将受到损害，并且与疾病的严重程度有关。假设3C：通过人类学和营养补充测量的生长失败将预测在接下来的24个月中前哨事件（腹水，静脉曲张出血，死亡和移植）的发作。 ii。 具体目标 关于引起胆道闭锁的因素或影响疾病进展的因素知之甚少。假设各种遗传，自身免疫和环境影响很重要。迄今为止，大多数研究都集中在具有文学学士学位的新生儿和幼儿上，但是拥有BA的年龄较大的孩子可以提供有关遗传学以及自然历史的重要信息。 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，以使研究人员能够解决上述假设，并以下相关目的： 具体目的1。确定与Ba病因有关的基因或基因 具体目的2。要确定在疾病进展中可能很重要的多态性，例如HLA多态性，以执行高分辨率HLA-A，B，C，C，DRB1，DRB3 DRB4，DRB5，DQA1，DQA1，DQB1，DQB1，DPA1，DPA1和DPB1在胆汁胆道Atresia的患者上拼写。 II.使用一种新型的计算机算法，该算法允许筛选大量HLA等位基因来检测胆道闭锁患者的共同表位。 iii。使用等位基因频率的传统分析和一种新颖的共享表位算法来评估HLA多态性在胆道闭锁的发病率和严重程度中的作用。 具体目标3。表征具有BA的老年人，未移植的孩子的自然历史。 iii。 背景和意义 肝外胆道闭锁（BA）是婴儿期的毁灭性疾病，在该状态下，肝或常见的胆管在肝炎肝炎到十二指肠的任何时候都存在闭塞或不连续性。 在未经治疗的情况下，这种情况在所有情况下会导致严重的肝损伤和死亡。 Kasai于1959年开发了肝脊骨骨术手术，仅在20％的受影响婴儿中才允许长期生存。 肝脏替代疗法的出现允许在许多其余婴儿中长期生存，但并非没有成本和发病率。 BA的估计发病率是18,000个活产中的8,000至1个。 美国儿童中所有肝脏移植的大约50％是针对每年BA固定140-180肝移植的婴儿。 尽管这种疾病具有毁灭性的性质及其治疗成本，但我们对其发病机理的了解知之甚少，也不了解与疾病进展有关的因素。 BA可能不是一种疾病，而是一种基本特异性疾病的表型，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）以刻板印象的方式反应这种表型。 直到我们对这些过程中涉及的机制有了更好的了解，就不会发生改善结果。