The Pittsburgh Cholestatic Liver Disease Consortium

描述（由申请人提供）：新生儿胆汁淤积性肝脏疾病，包括Alagille综合征、α-1抗胰蛋白酶缺乏症、胆汁酸合成缺陷、胆道闭锁、囊性纤维化、线粒体肝病和进行性家族性肝内胆汁淤积，导致儿童期发病率和死亡率显着，通常需要进行肝移植。一个美国临床中心看到了足够多的患者患有这些疾病，以允许对未解决的问题，包括病因和发病机制，诊断和治疗的最佳方法，以及影响疾病严重程度和预后的因素作出严格的回答。来自匹兹堡儿童医院匹兹堡胆汁淤积性肝病联盟的这项竞争性更新提案旨在继续儿童肝病研究网络（ChiLDReN）中正在进行的研究活动。这一更新资金的申请包括一个坚定的承诺，继续正在进行的研究工作和两个新的建议，一个基于现有的生物样本和临床数据库，另一个是一个新的临床试验。CHP的临床中心包括一组杰出的临床研究人员，他们在基础、转化和临床研究方面具有丰富的专业知识。迄今为止，ChiLDReN在正在进行的研究中的表现堪称典范，并充分利用了宾夕法尼亚州西部的人口基础以及CHP作为儿科肝病学和肝移植四级中心的独特转诊模式。将使用全基因组关联和动态贝叶斯网络分析来分析现有的生物样本库和临床数据库，以确定影响胆道闭锁手术反应的遗传和免疫因素。还提出了一项使用4-苯基丁酸酯治疗进行性家族性肝内胆汁淤积症（Byler病）的扩大访问开放标签单臂研究。这项试验的主要终点是安全性、耐受性和血清胆汁酸和其他肝病生化标志物的变化。

DESCRIPTION (provided by applicant): Neonatal cholestatic liver diseases including Alagille syndrome, alpha-1 antitrypsin deficiency, bile acid synthesis defects, biliary atresia, cystic fibrosis, mitochondrial hepatopathies and progressive familial intrahepatic cholestasis, lead to significant morbidity and mortality in childhood, frequently necessitating liver transplantation. N single United States clinical center sees a large enough number of patients with these disorders to permit a rigorous answer to unresolved questions including etiology and pathogenesis, optimal methods of diagnosis and treatment, and factors that influence disease severity and prognosis. This competitive renewal proposal from the Pittsburgh Cholestatic Liver Disease Consortium at Children's Hospital of Pittsburgh of UPMC seeks to continue ongoing research activities in the Childhood Liver Disease Research Network (ChiLDReN). This application for renewal funding includes a strong commitment to continuing the on-going research efforts and two new proposals, one based upon the existing biosamples and clinical database, the other a novel clinical trial. The clinical center at CHP includes an outstanding group of clinician investigators with well-documented expertise in basic, translational and clinical investigation. Performance to date in the on-going studies of ChiLDReN has been exemplary and has taken full advantage of the population base within Western Pennsylvania and the unique referral patterns to CHP as a quaternary center for Pediatric Hepatology and Liver Transplantation. The existing biosample repository and clinical database will be analyzed using genome wide associate and Dynamic Bayesian Network analyses to identify genetic and immunologic factors that influence response to surgery for biliary atresia. An expanded access open label single armed study of the use of 4-phenylbutyrate in the treatment of progressive familial intrahepatic cholestasis (Byler Disease) is also proposed. The major end-points of this trial will be safety, tolerability and change in serum bile acids and other biochemical markers of liver disease.