Continuation of ChiLDReN, the Childhood Liver Disease Research Network: Indiana U

描述（由申请人提供）：小儿肝病具有显著的发病率和死亡率。胆道闭锁占小儿肝移植的一半以上。新生儿胆汁淤积症的遗传原因包括Alagille综合征、α -1-抗胰蛋白酶缺乏症、进行性家族性肝内胆汁淤积症（PFIC）、胆汁酸合成缺陷、线粒体肝病和囊性纤维化。所有这些疾病都可能发展为肝硬化和终末期肝病。为了研究这些罕见疾病的诊断、进展和治疗，我们建议继续参与儿童研究网络，贡献和研究患有上述疾病的儿童。该网络的目标是纵向跟踪大量这些受试者，以便为有助于诊断、预测和治疗这些疾病的研究积累临床数据和生物标本。鉴定用于诊断和确定疾病进展的生物标志物是一个特别的目标。建立在这个非凡的CHILDREN数据库和生物储存库上的转化研究可以对发病机制、疾病调节剂和最终治疗产生新的见解。本中心将积极招募患有儿童疾病的患者，保留他们进行纵向随访，并为正在进行的研究做出贡献。囊性纤维化研究将继续评估超声在预测CF患儿肝硬化发展中的作用，并研究该疾病中肝硬化的进展。本中心将积极参与临床试验计划，1)研究肠道胆汁酸运输抑制剂对瘙痒症（胆汁淤积症最严重的致残性症状之一）的影响，2)研究一种新的维生素补充剂，以最佳地补充胆汁淤积症的脂溶性维生素缺乏。该网络的最终目标是了解更多的自然历史和发病机制，以便为儿童胆汁淤积性疾病的治疗和临床管理提供信息。IU中心提出的科学项目是囊性纤维化相关肝病的蛋白质组学研究。虽然大多数CF患者有一定程度的肝脏受累，但只有5-10%的患者发展为晚期肝硬化。该研究的目的是确定与CF肝硬化发展相关的血浆蛋白，并追踪该疾病的进展。识别晚期CF肝病的生物标志物将允许早期识别，并有机会选择这些儿童进行新的治疗药物的临床试验，这些药物可能会改善胆汁流动并改变疾病的进程。

DESCRIPTION (provided by applicant): Pediatric liver disease has significant morbidity and mortality. Biliary atresia accounts for more than half of pediatric liver transplants. Genetic causes of neonatal cholestasis include Alagille's syndrome, alpha-1- antitrypsin deficiency, Progressive Familial Intrahepatic Cholestasis (PFIC), bile acid synthetic defects, mitochondrial hepatopathies, and cystic fibrosis. All of these diseases can progress to cirrhosis and end stage liver disease. In order to study the diagnosis, progression, and treatment of these rare disorders, we propose to continue participation in the CHILDREN Research Network, contributing and studying children with the above diseases. The goals of the network are to follow large numbers of these subjects longitudinally to allow accumulation of clinical data and biospecimens for studies that can help diagnose, prognosticate for, and treat these diseases. Identification of biomarkers to use for diagnosis and to ascertain disease progression is a particular goal. Translational research founded on this remarkable CHILDREN database and biorepository can result in new insights regarding pathogenesis, disease modifiers, and ultimately treatment. Our center will recruit patients with CHILDREN diseases aggressively, retain them for longitudinal follow-up, and contribute to ongoing studies. The Cystic fibrosis study will continue to evaluate the role of ultrasound in predicting the development of cirrhosis i children with CF and to study the progression of cirrhosis in this disease. Our center will activel participate in clinical trials planned to 1)study the effect of an intestinal bile-acid transport inhibitor on pruritus, one of the most disabling symptoms of cholestasis, and 2) study a novel vitamin supplement targeted to optimally supplement fat-soluble vitamin deficiency in cholestasis. The ultimate goal of the network is to learn more about natural history and pathogenesis in order to inform therapy and clinical management of cholestatic diseases of children. The scientific project proposed by the IU center is a proteomic study of cystic fibrosis-related liver disease. While most patients with CF have some degree of liver involvement, only 5-10% develop advanced cirrhosis. The goals of the study are to identify plasma proteins that are associated with the development of CF cirrhosis and can track progression of that disease. Identification of biomarkers of advanced CF liver disease would allow early identification and the opportunity to select these children for clinical trials of novel therapeutic agents which might improve bile flow and change the course of the disease.