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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
AASLD/ALF Liver Scholar Award
Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
“Activation of complement system regulates epithelial injury and obstruction in biliary atresia”
Recent studies exploring the disease pathogenesis of biliary atresia (BA) have assigned functional roles to natural killer (NK) and CD8 T-cells in experimental biliary atresia. However, the molecular basis of disease initiating events remains largely undefined. Initial studies investigating the role of complement system in experimental biliary atresia have identified a vigorous activation of genes involved in the classical and alternative pathways of complement activation. Here, Dr. Shivakumar will determine whether 1) blocking complement activation by clinically used compounds and monoclonal antibodies attenuate bile duct injury and obstruction in a rotavirus (RRV)-induced murine model of BA, and 2) complement receptors C3aR and C5aR synergistically coordinate to regulate epithelial injury and duct obstruction in experimental BA. In preliminary studies, he found that postnatal RRV infection in newborn mice a) induced complement activation and increased serum levels of the bioactive peptides C3a and C5a, b) deposited complement activation fragments C3b/iC3b/C3c on intrahepatic and extrahepatic bile ducts, c) deposited membrane attack complex (MAC; C5b-9) on the injured areas of bile duct epithelium and d) partially resolved surface jaundice and acholic stools, improved survival and growth of RRV infected C5aR-deficient Balb/c mice. In the proposed experiments, he will determine whether inhibition of deposition of activated complement fragments C3b/iC3b/C3c will prevent duct injury and obstruction. Furthermore, Dr. Shivakumar will target the complement component C5 prior to the generation of C5a and C5b-9, both of which induce potent biological responses. In order to determine the reciprocal regulation of C3aR and C5aR in biliary atresia, Dr. Shivakumar proposes to block the activities of C5aR in C3aR–/– and C3aR in C5aR–/– mice by antibody and chemical inhibition of receptor activities. He also proposes to use C3aR–/–C5aR–/– double-deficient mice to obtain direct evidence of the synergistic role of C3aR and C5aR modulating epithelial injury and obstruction. Collectively, these studies will provide novel insights into the yet unexplored realms of complement activation in regulation of disease pathogenesis and identify therapeutic compounds to block the progression of hepatobiliary damage in biliary atresia.