Novel Approaches To The Pathogenesis Of Chronic Hepatitis C Virus Associated Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
The incidence of hepatitis C virus (HCV) infection is rapidly increasing in our community. This infection cannot be prevented by vaccination and the current treatments often fail. We believe that the novel approaches we are taking towards gaining an improved understanding of this disease process have the potential to lead to better therapies. We propose to examine disease progression using the new technology of gene array which scans thousands of genes simultaneously to find those most activated ....The incidence of hepatitis C virus (HCV) infection is rapidly increasing in our community. This infection cannot be prevented by vaccination and the current treatments often fail. We believe that the novel approaches we are taking towards gaining an improved understanding of this disease process have the potential to lead to better therapies. We propose to examine disease progression using the new technology of gene array which scans thousands of genes simultaneously to find those most activated. Our preliminary experiments indicated that one particular set of genes related to cell death is upregulated in HCV cirrhosis more than in other kinds of cirrhosis. We propose to pursue the diagnostic-prognostic potential of one of these molecules. Primarily this project will ask what kinds of genes are activated by HCV infection and at various stages of disease progression through to fibrosis and cirrhosis and following liver transplantation to better understand these processes. We believe that this research is likely to lead to a new understanding of hepatitis C associated liver disease that may lead to novel approaches to therapy.Read moreRead less
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 Fibroblast Activation Protein In Chronic Liver Injury
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
Chronic liver diseases, particularly those caused by Hepatitis B virus and Hepatitis C virus infection, are major causes of morbidity and mortality in our community. They are characterised by progressive scarring of the liver which finally leads to liver failure and the need in many cases for organ transplantation. We have identified a key molecule Fibroblast Activation Protein (FAP) that may play a key role and the process of liver fibrosis (scarring). The aims of the project are four fold: (1) ....Chronic liver diseases, particularly those caused by Hepatitis B virus and Hepatitis C virus infection, are major causes of morbidity and mortality in our community. They are characterised by progressive scarring of the liver which finally leads to liver failure and the need in many cases for organ transplantation. We have identified a key molecule Fibroblast Activation Protein (FAP) that may play a key role and the process of liver fibrosis (scarring). The aims of the project are four fold: (1) To characterise where and on what cells FAP is produced in the liver and whether FAP levels correlate with the development of fibrosis in human chronic liver diseases caused by either Hepatitis B or Hepatitis C virus infections. (2) To examine a mouse strain in which the FAP molecule is knocked out ie absent. This will tell us whether FAP itself is essential for the development of fibrosis. (3) To isolate the cells within the liver that make FAP and to examine how particular functions of these cells are modified by FAP. (4) To find out what particular molecules FAP acts upon to perform its functions. The achievement of these aims will greatly increase our understanding of this key enzyme and its role in chronic liver injury. This work can potentially lead to the development of specific inhibitors of FAP function designed to relieve liver damage.Read moreRead less
This project introduces a new biomarker in systemic lupus erythematosus termed an apotope. The aims are to study the diagnostic potential of an apotope of Ro60, a key target in lupus, together with its ability to initiate the disease and cause organ damage. The interaction of the Ro60 apotope with a novel protective factor called beta2-glycoprotein I will also be studied. These discoveries are likely to lead to new diagnostic tests and preventions for lupus and neonatal lupus.
The Effect Of Exercise On Insulin Resistance And The Adipokine Profile In Obese Versus Non Obese Patients With Hepatitis C
Funder
National Health and Medical Research Council
Funding Amount
$100,381.00
Summary
Chronic hepatitis C (CHC) infection and obesity are conditions of increasing prevalence. Untreated, CHC has significant long-term consequences including cirrhosis and liver failure, while obesity reduces the success of antiviral treatment. A tendency to develop diabetes in patients with CHC and obesity also leads to further medical complications. We aim to examine the effects of exercise on obesity and diabetes tendency in patients with CHC.
Profiling The Specificity Of The Neutralizing Antibody Response In People Who Have Long Term Protection From Developing Chronic HCV
Funder
National Health and Medical Research Council
Funding Amount
$372,972.00
Summary
Hepatitis C causes chronic liver disease in over 150 million people world-wide. In this study we will determine the qualities of the immune response that protect individuals from HCV infection and reinfection. The outcomes of this study will provide a pathway for the development of vaccines that elicit protective immune signatures.
Novel Bioinformatic Methods To Determine The Link Between Genomic Complexity Of Hepatitis Viruses And Liver Disease Phenotypes
Funder
National Health and Medical Research Council
Funding Amount
$605,859.00
Summary
Bioinformatics is a discipline concerned with the study of how information is stored and used in biological systems. Here we develop bioinformatic tools to study how hepatitis viruses evolve during an infection and how these infections cause severe liver diseases.
Understanding Rapid T-cell Clearance By The Liver: A Critical Step Towards Improved Liver Transplantation.
Funder
National Health and Medical Research Council
Funding Amount
$412,134.00
Summary
The liver has paradoxical properties: it is the site of effective immune responses to pathogens, but under some circumstances, it is known to induce harmless immune responses. Poor responses can be beneficial in a transplantation setting because, in the absence of immunosuppressive drugs, liver transplants are more readily accepted than other organ allografts. Not only are liver transplants well accepted, they can induce secondary acceptance of kidney or heart grafts from the same donor that wou ....The liver has paradoxical properties: it is the site of effective immune responses to pathogens, but under some circumstances, it is known to induce harmless immune responses. Poor responses can be beneficial in a transplantation setting because, in the absence of immunosuppressive drugs, liver transplants are more readily accepted than other organ allografts. Not only are liver transplants well accepted, they can induce secondary acceptance of kidney or heart grafts from the same donor that would otherwise be rejected. However, this ability of the liver to induce unresponsiveness may allow some viruses to persist, particularly , Hepatitis B and C. Four in every five patients infected with hepatitis C develop a chronic disease due to the inability of the immune system to clear the virus. Although it is known that white blood cells enter the liver and become unresponsive, little is known about the mechanisms that prevent an effective response. The CIA s work has been at the forefront of liver immunology and transplantation by demonstrating that the architecture and vasculature of the liver, and therefore the type of unique cellular interactions taking place within it, are essential to gain an understanding of its unique immunological properties. Using the CIB s unique protocols for solid-organ transplantation in rodents, we will provide evidence for a new mechanism that occurs at very early stages after antigen encounter in the liver. We propose to unravel this mechanism using well characterised transgenic mouse models and advanced analytical technology. We will determine the role of this mechanism in liver transplantation. Our preliminary data point to a very high chance of success. This project will have important implications for transplantation studies and for the development and treatment of food allergies and chronic hepatitis C and other of immune-mediated liver diseases.Read moreRead less
Polarized Epithelia And The Natural History Of Hepatitis Viruses
Funder
National Health and Medical Research Council
Funding Amount
$358,770.00
Summary
The viruses causing hepatitis in man must cross specialised cell layers in the body to reach the liver, and must again cross these cell layers and liver cells in order to be transmitted to subsequent hosts. This research will examine how each of the hepatitis viruses (HAV to HEV) are able to enter and exit the body, and the role that these mechanisms may play in the development of acute disease and of chronic infections with hepatitis B and C viruses. The findings will contribute to development ....The viruses causing hepatitis in man must cross specialised cell layers in the body to reach the liver, and must again cross these cell layers and liver cells in order to be transmitted to subsequent hosts. This research will examine how each of the hepatitis viruses (HAV to HEV) are able to enter and exit the body, and the role that these mechanisms may play in the development of acute disease and of chronic infections with hepatitis B and C viruses. The findings will contribute to development of improved methods for the prevention and control of viral hepatitis.Read moreRead less