Fibrogenesis, or scar formation, occurs as a response to injury in almost all organs. Liver fibrosis and subsequent cirrhosis remains a critical health problem in the United States and worldwide despite advances in therapy of chronic liver disease. Hepatic stellate cells (HSC) are the primary fibrogenic cells of the liver. Although there have been important advances in the understanding of HSC function in recent years, critical signaling mechanisms regulating HSC activity have not been completely understood. P2Y receptors are G protein coupled receptors for extracellular ATP and other nucleotides. P2Y receptors induce downstream cellular effects through inositol triphosphate (IP3)-mediated calcium signals. Recently, we reported that HSC express P2Y receptors, and that activation of these receptors induces fibrogenesis in HSC. We have now observed that HSC express IP3 receptors (IP3R) at distinct regions within HSC: the nucleus and cell extensions. This unique pattern of IP3R expression allows for distinct effects of P2Y receptor activation mediated by these two cellular compartments. We have also observed that blockade of P2Y receptors in the whole animal may prevent development of liver fibrosis, suggesting that signaling via P2Y receptors is an important mediator of liver fibrosis in disease states. Thus we propose that P2Y receptor activation induces liver fibrosis via multiple downstream effects in distinct subcellular compartments within HSC. We will test this hypothesis through the following three Specific Aims: 1. Determine the effects of P2Y receptor activation on the function of HSC in the nucleus. 2. Determine the effects of P2Y receptor activation on the function of HSC in cell extensions. 3. Identify whether blockade of P2Y receptors inhibits liver fibrosis. We believe that the results of the proposed experiments will lead to novel understanding of HSC function and may ultimately lead to the development of new pharmacologic approaches to the treatment of liver fibrosis. ? ? Public Health Relevance: Advanced liver fibrosis, leading to cirrhosis, is the most important cause of liver failure, leading to death in the absence of liver transplantation. Multiple therapeutic approaches have been proposed to prevent or reverse liver fibrosis; however, these have been stymied due to incomplete understanding of the basic mechanisms of liver fibrosis. In the proposed work, we will identify novel pathways that are important in the pathogenesis of liver fibrosis, which should in turn lead to new approaches to prevent or liver fibrosis in patients. ? ? ?
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