The molecular and functional characterisation of dimethylarginine dimethylaminohydrolase in acute-on-chronic liver failure, and determination of its role in portal hypertension (360G-Wellcome-087688_Z_08_Z)
The pathobiology of portal hypertension in response to liver injury in acute-on-chronic liver failure (ACLF) is yet to be determined. Recent work has demonstrated an association of liver inflammation and abnormalities in the metabolism of asymmetric dimethylarginine (ADMA) with portal hypertension and prognosis in ACLF. We hypothesise that altered ADMA metabolism in response to liver inflammation may propagate liver injury and portal hypertension in ACLF. This project will explore th e effect of manipulation of ADMA metabolism in determining the response to liver injury in rodent models of cirrhosis. Genetic and pharmacological manipulation of dimethylarginine dimethylaminohydrolase (DDAH), the major enzymatic route of ADMA elimination, will be used to modulate the degree of liver injury in response to bacterial lipopolysaccharide administration. The key aims of the project are: 1. To characterise the effects of superadded inflammation on DDAH gene expression, protein expression, cellular localisation and activity, and on portal haemodynamics, in cirrhosis. 2. To determine the molecular effects and changes in hepatic haemodynamics following pharmacological interventions that modulate inflammation, oxidative stress and DDAH-1 expression, in cirrhosis. 3. To determine whether DDAH-1 over-expression confers protection against increased liver injury and mortality following superadded liver inflammation in cirrhosis.
£185,766 01 Apr 2009