The Role Of CYP2E1 In Ethanol-mediated Protein Damage And Its Impact On Proteolytic Processing In The ER
Funder
National Health and Medical Research Council
Funding Amount
$179,239.00
Summary
Alcoholic liver disease (ALD) is the primary factor leading to mortality in chronic alcohol abusers. Alcoholic patients possess antibodies to damaged proteins in their bloodstreams, which indicates an underlying level of oxidative damage is occurring in their livers. The antibodies to these damaged proteins could trigger the destruction of liver cells. Alternatively, the damaged proteins themselves could result in cell death because of the way they are degraded in a particular compartment of the ....Alcoholic liver disease (ALD) is the primary factor leading to mortality in chronic alcohol abusers. Alcoholic patients possess antibodies to damaged proteins in their bloodstreams, which indicates an underlying level of oxidative damage is occurring in their livers. The antibodies to these damaged proteins could trigger the destruction of liver cells. Alternatively, the damaged proteins themselves could result in cell death because of the way they are degraded in a particular compartment of the cell, the endoplasmic reticulum (ER). An enzyme, CYP2E1, has been demonstrated to produce the types of chemicals that damage proteins and it is significantly increased in the liver by alcohol consumption. The current scientific proposal is aimed at determining whether CYP2E1 induction by ethanol contributes to ALD by perturbing the normal cellular disposal of damaged proteins in the ER.Read moreRead less
The Role Of Cyp2e1, Alcohol And HCV In Modulation Of Hepatocyte Homeostasis HCV Replication And Resistance To Interferon
Funder
National Health and Medical Research Council
Funding Amount
$455,520.00
Summary
Liver disease caused by alcohol consumption and hepatitis C virus (HCV) infection are major national health problems. Liver disease caused by HCV is greatly accelerated by alcohol consumption, however, the connection between the biochemical events initiated by alcohol, HCV and inflammatory pathways resulting in liver disease are not well understood. Preliminary studies have identified a link between an important alcohol-metabolising enzyme, Cyp2e1, HCV replication, oxidative stress and a powerfu ....Liver disease caused by alcohol consumption and hepatitis C virus (HCV) infection are major national health problems. Liver disease caused by HCV is greatly accelerated by alcohol consumption, however, the connection between the biochemical events initiated by alcohol, HCV and inflammatory pathways resulting in liver disease are not well understood. Preliminary studies have identified a link between an important alcohol-metabolising enzyme, Cyp2e1, HCV replication, oxidative stress and a powerful mediator of liver injury called tumour necrosis factor alpha. Furthermore we have shown that alcohol metabolism by Cyp2e1 results in an increase in HCV replication and negatively impacts on the anti-viral action of interferon. The studies contained within this proposal aim to build on these exciting new insights by attempting to identify new mediators and mechanisms of liver disease as a consequence of Cyp2e1 expression, alcohol and HCV replication. We will also examine the molecular mechanisms by which alcohol potentiates HCV replication. These studies will assist in developing therapeutic strategies that will benefit alcohol- and HCV-related liver disease.Read moreRead less