Biliary Atresia clinical Research Consortium

描述（由申请人提供）： 多中心协作联盟的创建为改善新生儿肝病儿童的生活提供了前所未有的机会。来自四个儿科医疗中心的临床中心申请描述了集体临床专业知识，合作研究经验和优秀的机构核心设施，这些设施需要成为该联盟的富有成效的贡献成员。本申请书建议以三种方式参加联合体： 1.临床数据收集：将开发统一、简洁的数据表格和电子收集系统来管理临床数据。相关临床数据和组织标本将提供给联盟。在本提案中合作的两个研究项目和四个临床项目可以提供大约25例胆道闭锁（BA）/年和12例新生儿肝炎（NH）/年的数据。 2.短期学习：利用现有的和积累的标本，我们将研究胆道闭锁和NH患者肝纤维化的发病机制，自然史和临床相关性。将使用Knodell肝纤维化量表的变体来确定加塞手术时的肝纤维化程度。免疫组织化学和原位杂交技术将用于定量肝纤维化和炎症的特异性分子标志物的表达。纤维化或特定染色模式的严重程度将与患者诊断和对加塞手术的反应相关联。 3.长期研究：为了鉴定胆道闭锁特有的或预测对加塞手术反应的蛋白质和基因表达模式，将在楔形肝活检以及通过激光捕获显微切割（LCM）分离的肝细胞和胆管上皮细胞中测定基因表达谱。现代蛋白质组学技术也将应用于血清样本，以鉴定受损肝脏合成和释放的蛋白质。类似于遗传谱，蛋白质的模式将与临床数据相关，以鉴定疾病特异性或预测预后的血清蛋白质模式。

DESCRIPTION (provided by applicant): The creation of a multi-center collaborative consortium provides an unprecedented opportunity to improve the lives of children with neonatal liver disease. This Clinical Center application from four pediatric medical centers describes the collective clinical expertise, collaborative research experience, and outstanding institutional core facilities needed to be productive contributing members to this consortium. This application proposes participation in the consortium in three ways: 1. Clinical Data Collection: A uniform, concise data form and electronic collection system will be developed to manage clinical data. Relevant clinical data and tissue specimens will be contributed to the Consortium. The two research programs and four clinical programs collaborating in this proposal can contribute data from approximately 25 new patients with biliary atresia (BA)/year and 12 patients with neonatal hepatitis (NH)/yr. 2. Short-term study: Using available and accumulated specimens, we will study the pathogenesis, natural history, and clinical correlates of hepatic fibrogenesis in patients with biliary atresia and NH. A variation of the Knodell hepatic fibrosis scale will be used to determine the extent of hepatic fibrosis at the time of the Kasai procedure. Immunohistochemical and in situ hybridization techniques will be used to quantify the expression of specific molecular markers of hepatic fibrosis and inflammation. The severity of fibrosis or specific staining patterns will be correllated with patient diagnosis and response to the Kasai procedure. 3. Long-term study: To identify patterns of protein and gene expression that are unique to biliary atresia or that predict response to the Kasai procedure, gene expression profiles will be determined in wedge liver biopsies as well as in hepatocytes and biliary epithelial cells isolated by laser capture microdissection (LCM). Modern proteomic techniques will also be applied to serum samples to identify proteins synthesized and released by the injured liver. Similar to the genetic profile, the pattern of proteins will be correlated with clinical data to identify patterns of serum proteins that are disease specific or predict prognosis.