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American Liver Foundation
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New York, New York 10006
AASLD/ALF Liver Scholar Award
The Children’s Hospital of Philadelphia/University of Pennsylvania, Philadelphia, Pennsylvania
“Mechanisms of Liver Fibrosis in Congenital Hepatic Fibrosis”
ARPKD is caused by mutations in the polycystic kidney and hepatic disease (PKHD1) gene encoding the protein fibrocystin/polyductin. The liver disease associated with this disorder is characterized by slowly progressing dense fibrosis surrounding dilated bile ducts, termed congenital hepatic fibrosis (CHF).
Fibrocystin/polyductin (FC/PD) is located in the primary cilia of cholangiocytes; however, the mechanism whereby FC/PD mutations induce liver fibrosis is not known. Dr. Wen’s data suggests that portal fibroblasts are the predominant fibroblastic cell type in this disease, not hepatic stellate cells. Monocyte chemotactic protein-1 (MCP-1), also known as CCL2, is a chemokine that has been described as a marker for liver fibrosis, especially biliary fibrosis. She found that it is highly expressed in CHF, but its role in ARPKD-associated liver disease is unclear.
The premise of this study is that biliary epithelial cells and portal fibroblasts behave abnormally in ARPKD/CHF, resulting in increased myofibroblastic differentiation of portal fibroblasts, leading to fibrosis. The experiments will try to 1) link abnormal FC/PD to up-regulation of MCP-1 by utilizing techniques to manipulate gene expression, with several previously identified targets as a potential mediator; 2) define the role of Kupffer cell on myofibroblastic differentiation of portal fibroblast by assaying for TGF-beta secretion under MCP-1 stimulation, and examining its functional role on hepatic fibrosis by utilizing Gadolinium depletion of Kupffer cells in the PCK rats; 3) determine the role of MCP-1 in Kupffer cell activation by utilizing MCP-1 inhibitor and examine its downstream effect on Kupffer cells activation and liver fibrosis in the PCK rats.
The proposed experiments will provide tremendous insight into the cellular interactions that are important in the fibrogenesis of this disease. It will also lead to better understanding of myofibroblastic differentiation of portal fibroblasts, an under-appreciated source of myofibroblasts in hepatic fibrosis. Dr. Wen hopes that the key roles of soluble and cellular factors in CHF may come to light and eventually allow us to better determine the suitability of various anti-fibrosis therapies currently under development for treatment of CHF and to potentially identify new targets for future advancement of anti-fibrosis therapy.