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.
Infant and pediatric cholestatic liver diseases are rare and individual hospitals cannot accumulate sufficient experience to make meaningful scientific contributions which are the basis for the management algorithms of these diseases. ChiLDREN will continue to facilitate the accrual of larger cohorts of patients with these rare diseases. The research study will explore the mechanisms that may cause the liver damage in biliary atresia.
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