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 potential therapies, the immediate translational impact of research in these disorders has never been greater. The 9 cholestatic disorders of the Childhood Liver Disease Research Network (ChiLDReN) have been studied in multi-centered research consortia at our Center for the past 15 years, during the last 10 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 and Executive Committees of ChiLDReN, the Chair for the CFLD studies, and Chairs of three protocols, among other roles. The objectives of this grant application in response to NIH RFA-DK-18-501 are to be chosen to be an active, collaborative and productive Clinical Center in the next version of ChiLDReN; to continue to enroll participants and complete, analyze and publish all of the ChiLDReN study protocols; to be an active participant in 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 data and biospecimens as illustrated by our Pilot Clinical & Feasibility Trial and Scientific Translational Strategy; to maintain leadership roles and Administrative Functions of ChiLDReN and the CFLD network; and to continue to provide PFIC/BRIC/ALGS Genotyping and Respiratory Chain Analysis expertise and services. Our Scientific Research Plan will propose a Pilot & Feasibility Clinical Trial comparing the effect of two intravenous lipid emulsions on liver function in children with biliary atresia and malnutrition who require parenteral nutrition. We will also propose a Translational Science Plan that investigates the crosstalk of activated neutrophils and hepatic stellate cells in the pathogenesis of biliary atresia using specimens from participants in PROBE and BASIC. In this way, our Clinical Center will enhance and build on the ChiLDReN goals of promoting clinical and translational research on pediatric liver diseases focusing upon elucidating the pathogenesis and natural history of these disorders and developing novel diagnostic and therapeutic strategies
This study will help to discover causes of liver disease, and develop new diagnostic tests and markers of disease activity and develop and test new treatments for infants and children with rare cholestatic liver diseases.
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