: The long-term objective of my research is to define the in vivo role of the receptor tyrosine kinase Ron in liver pathophysiology. Virtually nothing is known regarding the function of Ron in the liver. However, recent studies have shown that Ron signaling modulates hepatic responses in vivo. In order to define the in vivo significance of this receptor, my laboratory generated mice with a targeted ablation of the tyrosine kinase (TK) domain of Ron. These mice, referred to as TK-/- mice, display marked protection compared to control mice in a well characterized model of endotoxin (lipopolysaccharide, LPS) induced acute liver failure in galactosamine (GalN)-sensitized mice. In response to LPS/GalN, control mice exhibit profound hepatocellular injury evaluated by increases in serum aminotransferase levels and hemorrhagic necrosis of the liver. In contrast, the TK-/- mice have mild aminotransferase levels and relatively normal liver histology. The TK-/- mice also display a significant reduction in hepatocyte apoptosis compared to controls. Our preliminary data show that LPS/GalN treatment of TK-/- mice results in diminished levels of IFN-gamma an essential mediator of this injury model, as well as reduced amounts of select chemokines. The reduction in cytokine and chemokine production is associated with a decrease in the number of infiltrating neutrophils into the liver. Based on our preliminary data, this proposal will test the central hypothesis that Ron receptor signaling promotes the progression of acute liver failure by augmenting IFN-( and select chemokine production, leading to an increase in neutrophil recruitment, hepatocyte apoptosis and acute liver failure. In order to test this hypothesis, three specific aims are proposed.
Aim I will delineate the Ron-dependent cell type-specific mechanism responsible for augmenting IFN-( levels.
Aim II will define the Ron-dependent Kupffer cell-mediated mechanism required for promoting hepatocyte apoptosis.
Aim III will establish the requirement for Ron-dependent chemokine production in neutrophil mobilization to the liver. In total, we hope to understand the role of a potentially important receptor in liver biology with the hopes of impacting the treatment of human liver disease.
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