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

描述（由申请人提供）：婴儿和儿童的胆汁淤积性肝病是罕见但具有破坏性的疾病。其中，胆道闭锁（BA）是儿童终末期肝病最常见的病因。尽管进行了广泛的研究，但人们对BA发生的确切原因仍知之甚少。手术引流，BA治疗的主要方法，不幸的是，不到一半的时间有效，即使引流完成，大多数患者仍然会进展为肝硬化。因此，BA是世界上儿童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。手术引流后婴儿的表现与肝内胆道纤维化或肝硬化的程度有关。在快速发展的胆道纤维化区域内，有由祖细胞/干细胞组成的不规则胆管反应巢。这些导管反应，以及可能的祖细胞/干细胞，在许多其他先天性胆汁淤积性肝病中不存在，如Alagille综合征、进行性家族性肝内胆汁淤积(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PROM1（一种干细胞标记物），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。这一建议具有创新性，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。美国国立卫生研究院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包括BA在内的破坏性胆汁淤积性肝病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)继续参与儿童指导委员会和小组委员会的活动；继续筛选并招募符合条件的受试者参加各种研究（PROBE、BASIC、LOGIC、MITOHEP、PRIME）；继续举办一年一度的CHLA胆道闭锁日，开展家庭教育和交流；继续向该区域的保健社区开展教育外展活动；继续发展与该地区其他医疗保健提供者的临床合作；(2)翻译辅助研究这些表达PROM1的祖细胞/干细胞在BA相关的胆道纤维化中的作用(a)在实验性BA期间使用转基因小鼠细胞跟踪PROM1细胞(b)将血清和尿液中PROM1的水平与BA的诊断和纤维化程度联系起来。

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.