Novel therapeutic for Alcoholic Liver Disease

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DESCRIPTION (provided by applicant): Alcoholic Liver Disease (ALD) is a progressive liver disease that in advanced stages can result in cirrhosis and liver failure. ALD can be divided in various stages of development: (1) mild alcoholic liver injury, (2) steatosis, (3) alcoholic hepatitis, (4) alcoholic liver fibrosis and (5) cirrhosis. Liver fibrosis is a form of scar formation that is found in almost all patients with chronic injury to the liver. Over time it frequently progresses to cirrhosis, an end-stage lethal disease which is the seventh leading cause of death in the United States and afflicts hundreds of millions of people worldwide. There are several known causes for the development of cirrhosis, but alcohol intake remains the most important cause of liver cirrhosis in Western countries. Although several pharmacological therapies have been tried in patients with alcoholic liver disease, none of the therapeutics so far has shown consistent improvement in the course of alcoholic liver damage. Liver transplantation may be a treatment option of last resort for selected patients. There remains a great unmet medical need for new effective therapeutics for ALD. Members of the Rho family of small GTPases are essential modulators of adhesive signaling. One member of the family, the small GTPase Rac, has emerged as a promising new target for potential anti-fibrotic therapeutics in cirrhotic patients. Liu and co-workers in the laboratory of Dr. Andrew Leask e.g. generated mice with a fibroblast specific deletion of Rac1, and showed that such mice are resistant to bleomycin-induced skin fibrosis. Conversely, the sustained activation of Rac1 in hepatic stellate cells has been shown to promote liver fibrosis in mice. Taken together, there is an accumulating body of evidence that indicates that inhibition of Rac1 might be a novel approach to effectively prevent or reverse liver fibrosis. The natural organic molecule migrastatin has been identified as an inhibitor of tumor cell migration. Recently, several migrastatin analogs have been shown to inhibit Rac activation in cells and tumor metastasis in vivo murine models. This opens up the possibility of testing the effects of inhibition of Rac signaling on the development of liver fibrosis. In this study, we propose to provide direct in vivo evidence for Rac1 as a therapeutic target for alcoholic liver disease, by testing (1) the effects of a genetic ablation of Rac1 in fibroblasts and (2) the effects of pharmacological inhibition of Rac1 signaling on the development of liver fibrosis in mice. PUBLIC HEALTH RELEVANCE: Alcoholic Liver Disease (ALD) is a progressive liver disease that in advanced stages can result in liver failure. Cirrhosis, the end-stage of ALD is a lethal disease which is the seventh leading cause of death in the United States and afflicts hundreds of millions of people worldwide. There are several known causes for the development of cirrhosis, but alcohol intake remains the most important cause of liver cirrhosis in Western countries. No therapy has shown consistent improvement in the course of alcoholic liver damage so far, and there remains a great unmet medical need for new effective therapeutics for ALD. The small GTPase Rac1 has emerged as a promising new target for potential anti-fibrotic therapeutics in cirrhotic patients. We propose to test the involvement of Rac1 in the development of alcoholic liver disease, by studying the effects of genetic ablation of Rac1 or pharmacological inhibition of Rac1 signaling on the development of liver fibrosis mice. This might lead to new therapeutics for cirrhosis and other fibrotic disorders.