This application proposes ancillary studies to the NIDDK-Biliary Atresia Research Consortium (BARC). Biliary atresia, the most common cause of neonatal cholestasis, results from a fibro-inflammatory obstruction of extrahepatic bile ducts. Despite nearly uniform progression to end-stage cirrhosis, the variable rate of progression and response to treatment suggest the existence of unrecognized phenotypes that are based on the biology of disease. In view of the multifactorial pathogenesis of disease, we previously combined patient- based functional genomics and mechanistic studies in experimental biliary atresia and discovered a central role for proinflammatory immunity in disease pathogenesis. In preliminary studies for this application, we built a biliary atresia platform containing clinical, laboratory, histological, and genome-wide expression data for patients enrolled in a BARC prospective observational multi-center study and a corticosteroid trial. Initial analysis of this platform identified novel molecular subtypes that are biologically linked to histological features and relevant to the clinical outcome. Here, we propose a logical continuation of these studies with the overall aim of defining the biological basis for disease phenotypes and clinical outcomes of children with biliary atresia. To this end, we will pursue three aims: 1) To discover novel molecular subtypes of biliary atresia and define key regulatory networks, 2) To determine transcriptional predictors of favorable response to anti-inflammatory treatment, and 3) To define the cellular mechanisms regulated by inflammatory genes in biliary atresia. To achieve these aims, we will expand the biliary atresia platform with clinical/laboratory and gene expression data for patients enrolled in the BARC prospective observational study and the corticosteroid trial. We will then analyze the platform to validate the novel "inflammatory" and "fibrosing" subtypes and demonstrate their relevance to clinical course or progression of disease. To obtain insight into molecular networks regulating individual subtypes, we will apply functional and comparative genomics and use cell- and organ-based experimental systems to investigate how specific networks regulate pathogenesis of disease. Using the inflammatory signature, we will determine whether it is associated with an increased response rate to corticosteroid treatment. Finally, we will use complementary in vitro systems to explore cellular mechanisms of epithelial injury using mononuclear cells from patients with both subtypes. Collectively, the proposed experiments will create unparalleled opportunities to re-define the clinical spectrum of disease and to individualize treatments according to the patients'biological makeup.

Public Health Relevance

This project studies biliary atresia, the most common cause of chronic liver disease in children and the leading indication for pediatric liver transplantation in the United States. The overall aim is to define the biological basis of disease phenotypes and clinical outcomes. To achieve this aim, we will examine the liver gene expression profile at the time of diagnosis to identify new disease phenotypes, predictors of clinical outcome, and mechanisms of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083781-04
Application #
8321581
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$319,758
Indirect Cost
$106,586
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Tsai, Ellen A; Grochowski, Christopher M; Loomes, Kathleen M et al. (2014) Replication of a GWAS signal in a Caucasian population implicates ADD3 in susceptibility to biliary atresia. Hum Genet 133:235-43
Bessho, Kazuhiko; Mourya, Reena; Shivakumar, Pranavkumar et al. (2014) Gene expression signature for biliary atresia and a role for interleukin-8 in pathogenesis of experimental disease. Hepatology 60:211-23
Li, Jun; Razumilava, Nataliya; Gores, Gregory J et al. (2014) Biliary repair and carcinogenesis are mediated by IL-33-dependent cholangiocyte proliferation. J Clin Invest 124:3241-51
Dipaola, Frank; Shivakumar, Pranavkumar; Pfister, Janet et al. (2013) Identification of intramural epithelial networks linked to peribiliary glands that express progenitor cell markers and proliferate after injury in mice. Hepatology 58:1486-96
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