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American Liver Foundation Postdoctoral Research Fellowship Award
College of Medicine - University of Arkansas for Medical Sciences, Little Rock, Arkansas
“Dysregulation of CD73/ecto-5’-nucleotidase in liver fibrosis”
In the liver, extracellular nucleotides (e.g., ATP) and nucleosides (e.g., adenosine) are small endogenous molecules that control a variety of key cellular functions and/or processes such as glucose metabolism, bile formation and inflammation. To maintain tissue balance, liver cells express at their surface various enzymes called ectonucleotidases that are able to break down extracellular nucleotides and modulate their physiological effects. The liver ecto-5'-nucleotidase/CD73, which catalyzes the hydrolysis of adenosine monophosphate (AMP) to adenosine, is the primary determinant of tissue adenosine levels. In the normal liver, CD73 is essentially expressed by hepatocytes and portal mesenchymal cells. However, Dr. Fausther now has evidence that CD73 is up-regulated in hepatic stellate cells (HSC) and portal fibroblasts (PF) upon myofibroblastic differentiation. Rats with experimental liver fibrosis demonstrate strong ecto-5'-nucleotidase expression along fibrous septa. Furthermore, this up-regulation of CD73 is mediated at the transcriptional level. Since livers of mice deficient in ecto-5’-nucleotidase are resistant to experimental fibrosis, this enzyme may be of critical importance in liver fibrosis. Dr. Fausther’s goal is, using in vitro and in vivo models, to elucidate the role of ecto-5'-nucleotidase in the physiology of both hepatic stellate cells and portal fibroblasts. He will specifically evaluate the impact of ecto-5’-nucleotidase on the cell activation state and the fibrogenic potential of these two cell types. For this purpose, he will use primary HSC and PF isolated from livers of experimental wild-type and cd73-deficient mice and rats subjected to bile duct ligation (BDL) and carbon tetrachloride (CCL4) intoxication, as well as immortalized HSC. Dr. Fausther foresees that this project will help define new molecular aspects of the hepatic fibrogenic process and provide potential new therapeutic approaches to treat liver inflammation and fibrosis.