Liver regeneration is a unique repair response to damage where normally quiescent liver cells reenter the cell cycle and undergo cell division, regaining the damaged or lost tissue, while maintaining the differentiated function of the cells. Acute or chronic ethanol treatment impairs liver regeneration by mechanisms that remain poorly characterized. Deregulation of the liver's normal repair function may contribute to the development of alcoholic liver disease. The long-term objective of these studies is to characterize intracellular signaling events associated with liver regeneration and to assess how these signaling processes are affected by chronic ethanol treatment. Growth factors play an important role in the progression of liver regeneration. The onset of liver regeneration (priming) is associated with an activation of the growth factor receptors and their downstream signaling pathways. Our first specific aim is to characterize the activation of epidermal growth factor receptor signaling pathways in rat liver after partial hepatectomy and after priming of the liver with tumor necrosis factor-alpha or other treatments. We will determine how the priming-induced activation of growth factor response patterns is affected by chronic ethanol treatment. The second specific aim focuses on the role of apoptosis in the activation of growth factor responses. The early phase of liver regeneration may depend on the activation of apoptotic processes in the liver by cytokines and the appropriate cellular defense against these apoptotic signals. Mitochondria are a critical target for these signals. Chronic ethanol treatment affects mitochondrial function and promotes their susceptibility to pro-apoptotic signals. We will investigate how the balance of pro- and anti-apoptotic factors affects mitochondrial function during the onset of liver regeneration and how this balance is affected by chronic ethanol treatment. The third specific aim addresses the role of mitochondria in the energy stress associated with liver regeneration after partial hepatectomy. We presume that the enhanced energy demand activates intracellular signaling processes, resulting in changes in mitochondrial metabolism and enhanced oxidative stress. Chronic ethanol treatment diminishes the capacity of the mitochondria to respond to increased energy demand and increases oxidative stress. We will study how chronic ethanol treatment affects the energy state of the liver after partial hepatectomy, resulting in defects in the signals that are required for the onset of liver regeneration.
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