Liver failure is characterized by a loss of hepatocytes or hepatic function due to an acute liver insult or chronic liver disease. Liver failure is often accompanied by neurological complications, called hepatic encephalopathy, which lead to reduced quality of life and increased mortality in patients. Acute liver failure is characterized by hepatocyte necrosis that occurs at a rate that is too rapid for the liver to regenerate resulting in a loss of liver function. In contrast, chronic liver diseases are characterized with progressive fibrosis and cirrhosis that can generate liver failure as hepatocyte death occurs and hepatic regeneration is impaired due to aberrant cellular processes. During chronic liver disease, transforming growth factor ?1 (TGF?1) has been well classified as a factor involved with apoptosis, inflammation and liver fibrosis and therefore contributes to the progression of liver pathology. We recently demonstrated that TGF?1 also contributes to the pathogenesis of both acute liver failure and hepatic encephalopathy and that this signaling protein promotes increased endothelial cell permeability following acute liver injury. Unfortunately attempts to develop therapeutics that target TGF? signaling have failed clinical trials. Therefore, targeting proteins involved in activating TGF?1 and/or proteins that interact with TGF?1 signaling may prove to be better tolerated by patients. Taking this approach, the overall goal of this proposal is to investigate thrombospondin-1 (TSP-1), a homotrimeric glycoprotein that activates the propeptide form of TGF?1, and determine its contribution to pathology associated with acute and chronic liver failure. TSP-1 has been found to facilitate liver fibrosis through its interactions with TGF?1, though its actions during acute liver injury are not well classified. Our proposed specific aims will address two central hypotheses: (1) The hepatic expression of TSP-1 is elevated during acute liver failure leading to TGF?1 activation which drives hepatic inflammation, apoptosis, increased mortality and the development of hepatic encephalopathy; (2) Chronic liver failure is characterized by TGF?1 activation via TSP-1 which increases hepatic inflammation, fibrosis and other pathological processes associated with chronic liver disease. In this proposal, the pathogenesis of acute liver failure will be studied using a hepatocyte cell culture model as well as the azoxymethane-induced and acetaminophen-induced models of acute liver failure in mice. Chronic liver failure studies will employ rats that have undergone bile duct ligation surgery, a model of cholestasis and chronic biliary fibrosis with specific experiments targeted to assess cell-cell interactions in the liver. At the completion of this project, we expect to have determined the role of TSP-1 signaling on the pathological mechanisms involved with acute liver failure and chronic liver disease and will also determine the role of this signaling pathway in the development of hepatic encephalopathy. This will not only provide a greater classification of TSP-1 signaling during hepatic diseases, but could be used to identify potential therapeutic targets in patients.
The proposed research program is highly relevant to the VA mission and its successful completion will likely benefit the healthcare of United States Veterans. The risk of liver disease due to drug and alcohol abuse, as well as viral hepatitis, is increasing in the United States Veteran population. This is evident by a substantial increase in the prevalence of cirrhosis in United States Veterans over the last 15 years. Liver diseases remain one of the most common reasons for hospitalization and mortality in United States Veterans. This high rate of mortality is due to a relative lack of treatment options once liver disease progresses to liver failure with liver transplantation being the only effective treatment. Therefore, targeting thrombospondin-1, which has been shown to effect processes that are linked to liver failure, could identify new therapies for patients who suffer from acute liver injury or chronic liver disease.
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