Inflammatory Pathways To Liver Fibrosis In Non-alcoholic And Alcoholic Steatohepatitis: Reversal By NLRP3 Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$572,857.00
Summary
Nonalcoholic steatohepatitis (NASH) caused by obesity and diabetes made worse by alcohol, leads to cirrhosis. There is no effective treatment. In mice with NASH, MCC950, a novel drug that blocks NLRP3 (molecule that incites inflammation) reverses liver inflammation and possibly scarring. This proposal will test what activates NLRP3 in NASH, and whether blocking it completely with MCC950 or a new lasting longer inhibitor will dissolve severe liver scarring, and scarring made worse by alcohol.
Non-alcoholic steato-hepatitis (NASH) is a common disease of liver inflammation and scarring, which may progress to cirrhosis or liver cancer. While type 2 diabetes causes a higher rate of NASH and more rapid NASH progression the reasons for this are not clear. We have developed a novel animal model of NASH with diabetes added to dietary induced obesity. We show that a growth factor is elevated in the affected livers. We plan to block the growth factor to see if we can prevent NASH worsening.
MOLECULAR AND CELLULAR PATHOGENESIS OF HUMAN LIVER DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$4,928,323.00
Summary
n humans, chronic liver diseases cause cirrhosis of the liver in some but not all individuals. This leads to protracted ill-health, complications (fluid retention in the abdomen, confusion, bloodstream infections, kidney failure, liver cancer) resulting in hospitalisation, liver transplantation and premature death. In Australia, cirrhosis is an important cause of death and of years of potential life lost, while liver cancer has recently doubled and is predicted to treble by 2020. The common caus ....n humans, chronic liver diseases cause cirrhosis of the liver in some but not all individuals. This leads to protracted ill-health, complications (fluid retention in the abdomen, confusion, bloodstream infections, kidney failure, liver cancer) resulting in hospitalisation, liver transplantation and premature death. In Australia, cirrhosis is an important cause of death and of years of potential life lost, while liver cancer has recently doubled and is predicted to treble by 2020. The common causes are hepatitis C, fatty liver disorders, alcohol and hepatitis B; when 2 of these are present together, there is a higher risk of cirrhosis. This program aims to unravel the pathological processes which cause cirrhosis at the molecular and cellular levels, in order to understand why some people are at higher risk. These processes could result from genetic predisposition, other constitutional factors (age, gender) or from lifestyle factors (overnutrition, inactivity, alcohol). The 3 chief investigators from Westmead s Millennium Institute and the Centenary Institute of Royal Prince Alfred Hospital are international experts in hepatitis C, non-alcoholic steatohepatitis (NASH) and other fatty liver disorders, autoimmune hepatitis, liver transplantation, and scarring processes that lead to cirrhosis of the liver. The new knowledge that will result from these studies will be used to help prevent people developing severe forms of chronic liver disease, and for treating cirrhosis if it has already occurred.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
Exploring The Efficacy And Biobehavioural Basis Of Baclofen In The Treatment Of Alcoholic Liver Disease.
Funder
National Health and Medical Research Council
Funding Amount
$661,197.00
Summary
Alcoholic liver disease (ALD) is the main cause of death from alcohol consumption. Early detection of the disease and subsequent abstinence from alcohol can prevent death and disability. Current medications to help control alcohol consumption are not suitable for use in this patient population owing to the risk of liver side-effects. This study investigates the novel use of an existing medication, baclofen, to safely help maintain abstinence from alcohol in patients suffering from ALD.
A Randomised Controlled Trial Of N-acetylcysteine For The Treatment Of Alcohol Use Disorder
Funder
National Health and Medical Research Council
Funding Amount
$1,294,923.00
Summary
We urgently require new treatment strategies. Alcohol misuse is a leading cause of preventable death yet treatment options are limited. We will undertake the first human trial of N-acetylcysteine (NAC) for the management of alcohol use disorder (NAC-AUD). The NAC-AUD project will evaluate the efficacy and cost-efficacy of NAC to reduce alcohol consumption. The results will generate high level clinical evidence for a safe new treatment for a common life threatening disease.
Implementing And Enhancing Evidence-based Research And Practice In Hepatology
Funder
National Health and Medical Research Council
Funding Amount
$569,219.00
Summary
The overall aim of this proposal is to tackle unmet challenges in liver disease research. This will be achieved through (a) Population level programs to deliver new treatments for patients with hepatitis C; (b) Developing integrated care models to treat hepatitis B; (c) Developing population-level programs for liver cancer control; and (d) Identification of patients at risk of severe liver disease through understanding the genetic basis of disease progression.
I am infectious disease physician undertaking research on natural history and therapeutic strategies in viral hepatitis, including acute hepatitis C, chronic hepatitis C and chronic hepatitis B. The hepatitis C therapeutic research has a particular focus