Cholestatic liver diseases are among the most important liver disorders that occur in infants and children, leading to devastating morbidity and accounting for over 70% of liver transplants performed during childhood, thus posing a major public health burden. Although major advances in genetics of these disorders have been made over the past decade, few therapeutic options are available. Investigation of these disorders promises to advance scientific knowledge about hepatobiliary development, hepatocyte transporters, cholangiocyte biology, genetic regulatory networks, the neonatal immune response and mechanisms of injury, as well as the discovery of biomarkers of disease and testing of new diagnostic and therapeutic strategies. With the advent of next generation sequencing and genomics/epigenomics, disease modeling mathematical paradigms and a pipeline of new therapies, the potential translational impact of research in these disorders has never been greater. The 8 cholestatic disorders of the Childhood Liver Disease Research Network (ChiLDReN) have been studied in multi-centered research consortia at our Center for the past 11 years, during the last 5 years within ChiLDReN. Members of our Clinical Center at the University of Colorado Denver and Children's Hospital Colorado have played major leadership roles as the Chair of the Steering Committee of ChiLDReN and the Chair for the CFLD studies. The objectives of this grant application are for our site to be chosen as an active contributing Clinical Center in ChiLDReN;to continue to enroll new study subjects, follow current study subjects and retain subjects and fully implement, complete, analyze and publish all of the ChiLDReN study protocols;to be an active participant in the development of all new investigations, protocols and clinical trials initiated by the Network;to develop and propose new clinical and translational studies and ancillary studies that will utilize existing research subjecs, data and biospecimens, as illustrated by our proposed Scientific Research Plan;to oversee the CFLD studies and the CFLD network within ChiLDReN;to maintain leadership roles and some of the Administrative Functions of ChiLDReN and the CFLD network;and to continue to provide PFIC/BRIC Genotyping and Respiratory Chain Analysis expertise and services to the Network. Our Scientific Research Plan will elucidate the role of regulatory T-cells in human biliary atresia (BA), and determine if there are autoimmunity-associated SNPs in the gene FOXP3 present in BA and if these are related to the severity of BA. In these ways, our Clinical Center will enhance the ChiLDReN goals of promoting clinical and translational research in pediatric cholestatic liver diseases, focusing upon elucidating the pathogenesis and natural history and developing and testing novel therapeutics and clinical management strategies. Advances made by ChiLDReN should improve our understanding and clinical care of these important diseases and help to relieve an important public health burden.
This study will help to discover new diagnostic tests, markers of disease activity and develop and test new treatments for children with rare liver diseases and those who undergo liver transplantation.
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