Chronic heavy ethanol consumption has major adverse effects on the mammalian liver; namely, the induction of hepatocellular damage and impairment of the liver to regenerate following injury. In this context, there are profound biologic consequences for the host leading or contributing to progression of alcoholic liver disease, cirrhosis, and even hepatic failure. Therefore, it is important to understand at the molecular level, potential alterations in cellular signal transduction pathways that adversely affect the hepatocyte proliferative response, as well as those survival mechanisms critical for liver growth. It was determined that the insulin/IGF-1 signal transduction cascade, as mediated through the insulin receptor substrate-one (IRS-1) pathway, was important in the regulation of liver growth. The biologic consequences following activation of this cascade involved enhanced hepatocyte proliferation as well as inhibition of programmed cell death pathways. The net effect of chronic ethanol consumption was to inhibit the capacity of the liver to regenerate by altering growth factor signal transduction through the mitogen-activated protein kinase (MAPK) pathway. We also observed that PI3K was a key molecule targeted by ethanol. Preliminary studies suggest that reduction of activity may occur by both IRS-1 dependent and independent (as mediated by Phosphatase and Tension homolog [PTEN]) mechanisms. Since PI3K plays a critical role in cell survival as mediated through downstream Akt (PKB), our efforts will focus on a detailed analysis of these signaling cascades. More important, we have begun to identify ethanol sensitive downstream effector genes that are regulated through the growth factor mediated IRS-1 pathway and important in cell migration such as aspartyl (asparaginyl) hydroxylase (AAH); further characterization is a major goal of this research. We plan the following:
Specific Aim #1. Examine the effects of ethanol on PTEN as mediated by signals transmitted through PI3K.
Specific Aim #2. Akt is a key molecule in the regulation of programmed cell death pathways and we plan to evaluate its role on hepatocyte survival in the context of chronic ethanol abuse.
Specific Aim #3. Further, characterize the effect of ethanol on a critical downstream effector gene (AAH) upregulated through activation of the IRS- 1 signal transduction pathway. The biologic significance of this work as it applies to human disease is that ethanol may adversely affect specific signaling cascades related to both hepatocyte proliferation and survival as regulated by the IRS-1 dependent and independent signal transduction cascades in the liver. ? ?
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