Continuation of the Children's Hospital LA ChiLDREN Liver Research Center

描述（由申请人提供）：婴儿和儿童胆汁淤积性肝病是罕见但破坏性的疾病。其中，胆道闭锁（BA）是儿科终末期肝病最常见的原因。尽管进行了广泛的研究，但BA发生的确切原因并不清楚。手术引流是BA治疗的主要手段，但不幸的是，其效果不到一半，即使完成引流，大多数患者仍会进展为肝硬化。因此，BA是世界上儿科肝移植的主要适应症，占儿童移植的近50%，占整体肝移植的10%。一次或多次移植后的生存需要终身免疫抑制及其相关风险。婴儿手术后如何引流与肝内胆汁纤维化或肝硬化的程度密切相关。在快速发展的胆管纤维化区域内是由祖细胞/干细胞组成的颈静脉胆管反应巢。这些小管反应和可能的祖细胞/干细胞不存在于许多其他先天性胆汁淤积性肝病中，如Alagille综合征、进行性家族性肝内胆汁淤积症（PFIC）-1和-2、胆汁酸合成缺陷、线粒体肝病和特发性新生儿肝炎。这些细胞的作用尚不清楚，然而，初步研究表明，这些细胞表达PROMININ-1（PROM 1），一种干细胞标志物，并且这些细胞表现出与上皮细胞（如肝细胞或胆管细胞）以及成纤维细胞共同的特征。此外，初步数据表明，这些细胞产生胶原蛋白，这是器官纤维化的关键成分。该建议是创新的，因为它将注意力集中在迄今为止尚未在BA中研究或表征的新细胞群上。NIH资助的儿童肝病研究和教育网络（ChiLDREN）的总体目标是改善患有破坏性胆汁淤积性肝病（包括BA）的婴儿和儿童的生活。为了实现这一目标，洛杉矶儿童医院（CHLA）建议（1）继续参与ChiLDREN指导委员会和小组委员会的活动;继续筛选合格受试者并将其招募到各项研究中（PROBE、BASIC、LOGIC、MITOHEP、PRIME）;继续开展每年一度的CHLA胆道闭锁日活动，开展家庭教育和建立联系;继续向该地区的医疗保健界开展教育宣传;继续与该地区的其他医疗保健提供者开展临床合作;以及（2）关于这些表达PROM 1的祖细胞/干细胞在与BA相关的胆汁纤维化中的作用的转化辅助研究（a）在实验性BA期间使用转基因小鼠细胞追踪PROM 1细胞和（B）将血清和尿液中的PROM 1水平与BA的诊断和纤维化程度相关联。

DESCRIPTION (provided by applicant): Cholestatic liver diseases in infants and children are rare but devastating diseases. Amongst them, biliary atresia (BA) is the most common cause of pediatric end-stage liver disease. Despite extensive research, why exactly BA occurs is not well understood. Surgical drainage, the mainstay of BA treatment, unfortunately works less than half the time and even when drainage is accomplished, most patients still experience progression to cirrhosis. As such, BA is the leading indication for pediatric liver transplantation in the world, accounting for nearly 50% of transplants in children and 10% of liver transplants overall. Survival after one or more transplantations requires life-long immunosuppression with its associated risks. How infants do after surgical drainage is tied to the extent of intrahepatic biliary fibrosis or cirrhosis. Within regions of rapidly evolving biliary fibrosis are nests of irrgular biliary ductular reactions, comprised of progenitor/stem cells. These ductular reactions, and presumable the progenitor/stem cells, are not present in many other congenital cholestatic liver diseases, such as Alagille syndrome, Progressive Familial Intrahepatic Cholestasis (PFIC) -1 and -2, bile acid synthesis defects, mitochondrial hepatopathies, and idiopathic neonatal hepatitis. The role of these cells is not known, however, preliminary studies indicate that these cells express PROMININ-1 (PROM1), a stem cell marker, and that these cells exhibit characteristics in common with both epithelial cells, such as hepatocytes or bile duct cells, as well as fibroblasts. Furthermore, preliminary data indicate that these cells produce collagen, which is the key component of organ fibrosis. This proposal is innovative because it focuses attention on a novel cell population which to date has not been studied or characterized in BA. The overall objective of the NIH-funded Childhood Liver Disease Research and Education Network (ChiLDREN) is to improve the lives of infants and children with devastating cholestatic liver disease including BA. In order to achieve this objective, Children's Hospital Los Angeles (CHLA) proposes to (1) continue participating in ChiLDREN Steering Committee and subcommittee activities; continue screening and enrolling eligible subjects into the various studies (PROBE, BASIC, LOGIC, MITOHEP, PRIME); continue the annual CHLA Biliary Atresia Day for family education and networking; continue with educational outreach to the healthcare community in the region; continue developing clinical collaborations with other healthcare providers in the region; and (2) a translational ancillary study on the role of these PROM1-expressing progenitor/stem cells in the biliary fibrosis associated with BA (a) using transgenic mouse cell tracking of PROM1 cells during experimental BA and (b) correlating serum and urine levels of PROM1 with the diagnosis of BA and the degree of fibrosis.