The Cell and Molecular Biology of Myofibroblasts in Hepatic Fibrosis

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DESCRIPTION (provided by applicant): Liver fibrosis represents the body's response to chronic liver injury and appears to be similar mechanistically to the fibrogenic response in other organs. The fibrogenic process is a complicated one, but at the same time, highly integrated. The pathobiology of fibrogenesis includes increased production of extracellular matrix proteins, tissue contraction, and ultimately, disruption of normal tissue structure architecture. It has been well established over the last 2 decades that in the liver, a key cellular effector of this processis the hepatic stellate cell. Hepatic stellate cells exhibit a further unique characteristic in that ater injury, they become activated and transform into a myofibroblast. This myofibroblastic transition is characterized not only by increased production of extracellular matrix (resulting in the fibrogenic response to injury), but also the expression of large quantities of the actin isoform, smooth muscle ? actin (also known as Acta2). The result of ongoing stellate cell activation and hepatic fibrogenesis is cirrhosis, which results in many serious clinical complications such as impaired hepatocellular function, hepatocellular carcinoma, portal hypertension with its associated disorders including ascites and gastrointestinal hemorrhage. Because of their central role in fibrogenesis and our goal to better understand the pathogenesis of liver fibrosis, specific area of investigation in our laboratory has been in the cell and molecular biology of hepatic stellate cells during the activation and wounding response. We have in particular been focused on the stellate cell myofibroblastic transition, and in this application focus on smooth muscle ? actin molecular biology - and its associated cell biology. Thus, in an effort to better understand smooth muscle ? actin biology in stellate cells, we have developed a series of tools, including ideal cell and animal systems that have allowed us to extend our work in a highly novel direction, to include exploration of the regulation of the stellate cell smooth muscle geneti program and the role of smooth muscle ? actin in fibrogenesis. The proposed studies have substantial implications for wound healing biology not only in the liver as well, but also in other organ systems. Finally, we propose a potential translational therapeutic approach as a result of the work with smooth muscle ? actin.