Cirrhosis is the 12th leading cause of death in the United States, yet effective treatments to prevent or treat cirrhosis are lacking. The primary manifestation of cirrhosis is advanced fibrosis, or scar formation, in the liver. Hepatic stellate cells are important mediators of liver fibrosis, yet many aspects of hepatic stellate cell biology are poorly understood. One thing that is well characterized is the myofibroblastic differentiation of hepatic stellate cells, often termed activation, in the diseased liver. The purpose of the experiments proposed in this grant application is to identify novel pathways by which intracellular calcium and its effector molecules regulate myofibroblastic hepatic stellate cells. I the first aim, we will investigate the role of the calcium effector molecule calmodulin kinase II i hepatic stellate cell function. In the second aim, we will identify mechanisms by which stored components favoring scar formation are released from myofibroblastic hepatic stellate cells. In the third and final aim, we will test the role of the enzyme CD73/5'-ectonucleotidase in the regulation of hepatic stellate cell function. The long-term goals of this project are to identify novel pathways for the prevention and/or treatment of cirrhosis in patients with chronic liver disease.

R56DK076735

2006-12-01

2016-08-31