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, posing a major public health burden. In cholestasis, impairment of bile flow leads to the accumulation of hepatotoxic bile acids, cholesterol and other compounds that produce liver injury and complications such as pruritus and xanthomas;nutritional deficiencies caused by fat and fat-soluble vitamin malabsorption;and progressive hepatic fibrosis, portal hypertension and eventually chronic liver failure. Investigation of these disorders promises to advance scientific knowledge about liver development, pathophysiology and mechanisms of injury, as well as the discovery of biomarkers of disease and development and testing of new diagnostic and therapeutic strategies. A group of these disorders has been studied at our Center for the past 6 years within the Biliary Atresia Research Consortium (BARC) and the Cholestatic Liver Disease Consortium (CLiC), and include biliary atresia, idiopathic neonatal hepatitis, alpha- i-antitrypsin deficiency, Alagille syndrome, progressive familial intrahepatic cholestasis, bile acid synthesis defects, mitochondrial hepatopathies, and, most recently, cystic fibrosis liver disease. Members of our BARC and CLiC Clinical Centers at the University of Colorado Denver and The Children's Hospital have played major leadership roles as the Chair of the Steering Committee of BARC, the Principal Investigator and Chair of CLiC, and the Study Chair for the CFLD studies. The obiectives of this grant application are to become a Clinical Center and Administrative Core in the newly merged Childhood Liver Disease Research and Education Network;to continue to enroll participants and fully implement, complete and publish all of the ongoing BARC and CLiC study protocols, including the corticosteroid trial in biliary atresia;to participate in all new investigations, protocols and clinical trials initiated by the Network;to develop and propose new clinical studies and ancillary/pilot studies;to participate in training of research fellows and education of the public;to function as the Administrative Core of ChiLDREN;and to continue as one of the Genetic Cores and the Respiratory Chain Core. In this way, our Clinical Center will participate in the ChiLDREN goals of discovering new diagnostics, etiologies and treatment options for children with cholestatic liver diseases and to train the next generation of investigators in pediatric liver diseases. Relevance: This study will help to discover new diagnostic tests and treatments for children with liver disease and those who undergo liver transplantation. We will also train the researchers of the future who will study these rare diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK062453-11
Application #
8327873
Study Section
Special Emphasis Panel (ZDK1-GRB-S (M1))
Program Officer
Sherker, Averell H
Project Start
2002-09-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
11
Fiscal Year
2012
Total Cost
$1,128,188
Indirect Cost
$96,628
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Loomes, Kathleen M; Spino, Cathie; Goodrich, Nathan P et al. (2018) Bone Density in Children With Chronic Liver Disease Correlates With Growth and Cholestasis. Hepatology :
Bull, Laura N; Pawlikowska, Ludmila; Strautnieks, Sandra et al. (2018) Outcomes of surgical management of familial intrahepatic cholestasis 1 and bile salt export protein deficiencies. Hepatol Commun 2:515-528
Ng, Vicky L; Sorensen, Lisa G; Alonso, Estella M et al. (2018) Neurodevelopmental Outcome of Young Children with Biliary Atresia and Native Liver: Results from the ChiLDReN Study. J Pediatr 196:139-147.e3
Alonso, Estella M; Ye, Wen; Hawthorne, Kieran et al. (2018) Impact of Steroid Therapy on Early Growth in Infants with Biliary Atresia: The Multicenter Steroids in Biliary Atresia Randomized Trial. J Pediatr 202:179-185.e4
Bezerra, Jorge A; Wells, Rebecca G; Mack, Cara L et al. (2018) BILIARY ATRESIA: Clinical and Research Challenges for the 21st Century. Hepatology :
Sundaram, Shikha S; Mack, Cara L; Feldman, Amy G et al. (2017) Biliary atresia: Indications and timing of liver transplantation and optimization of pretransplant care. Liver Transpl 23:96-109
Carey, Alexandra N; Zhang, Wujuan; Setchell, Kenneth D R et al. (2017) Hepatic MDR3 expression impacts lipid homeostasis and susceptibility to inflammatory bile duct obstruction in neonates. Pediatr Res 82:122-132
Wang, Kasper S; Tiao, Greg; Bass, Lee M et al. (2017) Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis. Hepatology 65:1645-1654
Tang, Vivian; Cofer, Zenobia C; Cui, Shuang et al. (2016) Loss of a Candidate Biliary Atresia Susceptibility Gene, add3a, Causes Biliary Developmental Defects in Zebrafish. J Pediatr Gastroenterol Nutr 63:524-530
Sokol, Ronald J (2016) Molecular Chaperones as Therapy for PFIC: Not So Fast! J Pediatr Gastroenterol Nutr 62:360-2

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