Studies Of The Role Of The Hepatocyte In The Response To HCV Infection
Funder
National Health and Medical Research Council
Funding Amount
$513,294.00
Summary
Infection with hepatitis C (HCV) affects 120 million individuals worldwide, and over 200,000 in Australia. HCV-related liver disease is the most common indication for liver transplantation in Australia and rates of HCV-related liver failure and hepatocellular cancer are predicted to increase as the HCV population ages. A new test for the IL28B gene, has shown to be the strongest predictor of cure after treatment. The mechanism of this association is unknown and is the subject of this grant.
Inflammatory Mediators Of Liver Injury In Chronic Hepatitis C
Funder
National Health and Medical Research Council
Funding Amount
$349,336.00
Summary
Presently, liver disease from chronic hepatitis C and obesity represents a major health problem. Overall, approximately 50% of Australians with chronic hepatitis C are obese and these patients are at significantly increased risk of rapidly progressing to liver failure. It is now recognized that fat derived factors play an important role in regulating inflammatory responses. This grant proposal aims to gain insight into how liver and fat derived inflammatory factors interact to promote increased ....Presently, liver disease from chronic hepatitis C and obesity represents a major health problem. Overall, approximately 50% of Australians with chronic hepatitis C are obese and these patients are at significantly increased risk of rapidly progressing to liver failure. It is now recognized that fat derived factors play an important role in regulating inflammatory responses. This grant proposal aims to gain insight into how liver and fat derived inflammatory factors interact to promote increased liver damage in chronic hepatitis C and obesity.Read moreRead less
Fine Positioning And Effector Function Of T Cells Recruited To The HCV Infected Liver
Funder
National Health and Medical Research Council
Funding Amount
$321,973.00
Summary
The majority of patients who become infected with hepatitis C virus (HCV) are unable to mount an effective immune response and clear the virus and therefore develop lifelong (chronic) infection. The persistence of virus in the liver of patients with chronic infection results in the recruitment of significant numbers of immune cells, notably T cells, from the bloodstream into the liver where they are involved in both viral control (but not viral clearance) and liver injury. The level of tissue in ....The majority of patients who become infected with hepatitis C virus (HCV) are unable to mount an effective immune response and clear the virus and therefore develop lifelong (chronic) infection. The persistence of virus in the liver of patients with chronic infection results in the recruitment of significant numbers of immune cells, notably T cells, from the bloodstream into the liver where they are involved in both viral control (but not viral clearance) and liver injury. The level of tissue injury observed and the speed of disease progression may be linked to the type of T cells recruited, their function, and their position in the liver. The aims of this project are to determine the factors involved in the fine positioning of T cells in the liver and establish a relationship between T cell recruitment, function, and progression of HCV disease in the liver.Read moreRead less
Significance Of Microparticles In The Pathogenesis Of Liver Ischemia Reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$643,958.00
Summary
The overall aim of the project is to investigate the significance of microparticles in liver ischemia reperfusion injury (IRI). IRI causes damage to donor livers stored in preparation for liver transplantation. We postulate that microparticles released from the liver are critical in this form of injury. The expected outcomes are novel insights into liver IRI with the aim of developing new approaches to prevent liver damage during liver surgery, transplantation and shock.
Cholestasis And Hepatocyte Injury In Chronic Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$615,967.00
Summary
The aim of this project is to understand the consequences of long-term cholestasis or impaired bile excretion/flow on normal liver cells (hepatocytes) and to test whether specific bile acids can cause irreversible damage to hepatocytes leading to their transformation into pre-malignant cells and hepatocellular carcinoma (primary liver cancer). The results from this project will inform new strategies in screening, prevention and treatment of liver cancer in children and adults with cholestasis.
P53 And Hepatocyte Proliferation In Chronic Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$331,360.00
Summary
The aim of this project is understand how loss of control of p53, a tumour suppressor gene, in liver cells causes the transformation of normal liver cell (hepatocyte) to ‘rouge’ pre-cancerous cells in hepatocellular carcinoma (HCC) or primary liver cancer. We will test novel therapies to restore p53 function in liver cells in order to prevent or retard the development of HCC in patients with cirrhosis and those ‘at risk’ of this rapidly increasing fatal cancer in Australia.
MERTK Receptor Tyrosine Kinase: A Novel Therapeutic Target For Liver Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$870,972.00
Summary
Hepatic fibrosis is the principal cause of liver-related morbidity and mortality, for which there are no effective therapies. Thus, there is an urgent and unmet need to identify new targets to treat liver fibrosis. We have demonstrated for the first time, that liver fibrosis correlates with elevated hepatic expression of MERTK, a receptor tyrosine kinase. This project will explore whether MERTK function can be exploited to target and reverse liver fibrosis
The Role Of MBOAT7 In Hepatic Inflammation: Implications For Therapy
Funder
National Health and Medical Research Council
Funding Amount
$848,340.00
Summary
When a fatty liver progresses to develop inflammation, patients are at-risk of liver-related morbidity and death. Currently, there are no effective therapies. From human studies, we have discovered that a lipid modifying enzyme (MBOAT7) profoundly regulates liver inflammation. In this proposal, we will obtain a detailed understanding of how the activity of this pathway modulates inflammation. We expect to show that MBOAT7 is a novel ‘druggable’ pathway for the treatment of liver inflammation.
Molecular And Cellular Pathogenesis Of Nonalcoholic Steatohepatitis: Insights From Human Studies
Funder
National Health and Medical Research Council
Funding Amount
$215,500.00
Summary
Nonalcoholic steatohepatitis (NASH) is the commonest cause for liver disease in Australia. On liver biopsy it is characterised by changes similar to that induced by alcohol, but occurs in individuals who consume minimal amounts of alcohol. The risk factors for the development of NASH include obesity, type II diabetes and hyperlipidemia. As the prevalence of obesity and diabetes are rapidly increasing in Australia, it is evident that NASH will become of major public health concern in the future. ....Nonalcoholic steatohepatitis (NASH) is the commonest cause for liver disease in Australia. On liver biopsy it is characterised by changes similar to that induced by alcohol, but occurs in individuals who consume minimal amounts of alcohol. The risk factors for the development of NASH include obesity, type II diabetes and hyperlipidemia. As the prevalence of obesity and diabetes are rapidly increasing in Australia, it is evident that NASH will become of major public health concern in the future. In those that develop liver disease from NASH, a proportion (10-30%) will develop advanced liver scarring leading to significant morbidity and mortality. The overall aim of this proposal is therefore to provide insight into why some people with fatty liver disorders develop NASH and to determine the basis for disease progression in this condition. Over the last decade, work at the Storr Liver Unit in a nutritional animal model of NASH has suggested potential mechanisms for disease progression in NASH. This proposal seeks to determine whether such mechanisms operate in human NASH by conducting studies in a large cohort of well chracterised patients with this disorder. Advances in molecular and cellular biology now permit such studies by anaylsis of small quantities of tissue such as that obtained at the time of liver biopsy. In this proposal we will examine both serum and liver tissue to characterise the role of oxidative stress (the biologic equivalent of rusting), the host immune response, liver cell injury and damage to the metabolic machinery within cells as determinants of diease severity in NASH. It is anticipated that these studies will provide the most comprehensive data to date on the pathogenesis of NASH and should suggest potential therapeutic targets for treating this condition.Read moreRead less
The Role Of The Hepatocyte And EMMPRIN In Liver Injury
Funder
National Health and Medical Research Council
Funding Amount
$607,487.00
Summary
This research plan investigates the role of the hepatocyte, the principal functional cell within the liver in the development of liver disease. Liver injury can result in end-stage scaring known as cirrhosis as well as leading to liver cancer. Our research aims to identify strategies for reversing the fibrotic process and result damage to the liver