Biliary atresia, the most common infantile liver disease, is characterized by occlusion of the entire biliary tree. The etiology of biliary atresia s unknown, but a developmental anomaly of the biliary system or the progressive destruction of the biliary system due to viral infection or environmental factors have been proposed to responsible for the disease. In order to understand the genetic factors that contribute to the pathogenesis of biliary atresia, we undertook forward genetic and chemical screens to identify previously unappreciated genes and pathways that are responsible for biliary system formation in zebrafish. We will investigate the molecular mechanisms underlying biliary atresia-like phenotypes in zebrafish by using our innovative computational algorithms to quantify subtle difference in three-dimensional biliary branching patterns. Building on this work, we will then extend our studies to human biliary atresia patient samples to investigate the pathology. Successful execution of this collaborative scientific endeavor promises to develop important new scientific insights into biliary system formation, and may have profound implications for our understanding of the pathology of biliary atresia.

Public Health Relevance

Identifying and understanding the molecular mechanisms underlying the etiology of biliary atresia offers new opportunities for therapeutic intervention. This study utilizes forward genetic approaches to investigate the genetic factors that are responsible for biliary system formation and the pathogenesis of biliary atresia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK103637-01A1
Application #
8960206
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Karp, Robert W
Project Start
2015-07-25
Project End
2020-06-30
Budget Start
2015-07-25
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
$356,625
Indirect Cost
$131,625
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Gromovsky, Anthony D; Schugar, Rebecca C; Brown, Amanda L et al. (2018) ?-5 Fatty Acid Desaturase FADS1 Impacts Metabolic Disease by Balancing Proinflammatory and Proresolving Lipid Mediators. Arterioscler Thromb Vasc Biol 38:218-231
Dimri, Manali; Bilogan, Cassandra; Pierce, Lain X et al. (2017) Three-dimensional structural analysis reveals a Cdk5-mediated kinase cascade regulating hepatic biliary network branching in zebrafish. Development 144:2595-2605