The Role Of Vasoactive Hormones In Progressive Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$453,750.00
Summary
Cirrhosis of the liver is a leading cause of morbidity and mortality in our community and its prevalence is rising due to the increasing impact of chronic viral hepatitis infection. While the advent of effective antiviral therapies will have some benefit in reducing this disease burden, there remains a major need to develop treatments that can prevent and treat cirrhosis of the liver and its clinical sequelae. We believe that overactive hormone systems may play a role in disease of the liver. Th ....Cirrhosis of the liver is a leading cause of morbidity and mortality in our community and its prevalence is rising due to the increasing impact of chronic viral hepatitis infection. While the advent of effective antiviral therapies will have some benefit in reducing this disease burden, there remains a major need to develop treatments that can prevent and treat cirrhosis of the liver and its clinical sequelae. We believe that overactive hormone systems may play a role in disease of the liver. The planned studies will involve compounds that block the formation or the action of hormones which cause scarring of the liver. The results may lead to new treatments for cirrhosis of the liver.Read moreRead less
Novel Genes And Protein In Non-alcoholic Fatty Liver Disease: Potential Basis Of A Serum-based Assessment Of Disease Sta
Funder
National Health and Medical Research Council
Funding Amount
$200,000.00
Summary
The most common cause of elevated liver function tests is non-alcoholic fatty liver disease (NAFLD). NALFD is a spectrum of disease ranging from steatosis, to non-alcoholic steatohepatitis (NASH), a condition associated with the development of fibrosis in the majority of individuals. Approximately 20% and 3% of adults are affected with NAFLD and NASH, respectively, and NAFLD is expected to become the next major liver epidemic facing the western world, far exceeding the prevalence of chronic infe ....The most common cause of elevated liver function tests is non-alcoholic fatty liver disease (NAFLD). NALFD is a spectrum of disease ranging from steatosis, to non-alcoholic steatohepatitis (NASH), a condition associated with the development of fibrosis in the majority of individuals. Approximately 20% and 3% of adults are affected with NAFLD and NASH, respectively, and NAFLD is expected to become the next major liver epidemic facing the western world, far exceeding the prevalence of chronic infection with the hepatitis C virus. We obtained liver biopsies from patients with NAFLD, 80% of whom had NASH, and determined the expression profile analysis of each subject using 19,200 element microarrays. Our data demonstrates the concordant differential expression of 130 genes, in subjects with NAFLD that were categorizes into 6 major metabolic and regulatory pathways. Many of these genes represented uncharacterised genes. Utilising an extensive bioinformatics approach we have been able to define the genes and their protein product. The use of these proteins as a diagnostic tool for the detection of NAFLD forms the basis of a provisional patent application. However, measurements of protein levels in tissue and sera from patients with NAFLD are needed for the development of a diagnostic method. Such information would also provide significant insight into the pathogenesis of NAFLD. The AIMS are: 1) Production of antibodies against proteins encoded by candidate genes Expression profile of candidate genes 3) Expression of proteins encoded by candidate genes in patients with NAFLDRead moreRead less
Regulation Of Angiotensin-Converting Enzyme -2 Expression In Liver Injury
Funder
National Health and Medical Research Council
Funding Amount
$302,764.00
Summary
Very recent studies suggest Angiotensin-Converting Enzyme-2 (ACE2) a newly discovered enzyme, normally undetectable in the liver is markedly increased in liver disease in both man and rats. We have recently identified human liver cell lines that endogenously express ACE2 giving us a unique opportunity to investigate the function of this enzyme. The aim of the present project is to provide further insights into the role of ACE2 in liver disease by determining the regulation, location and transpor ....Very recent studies suggest Angiotensin-Converting Enzyme-2 (ACE2) a newly discovered enzyme, normally undetectable in the liver is markedly increased in liver disease in both man and rats. We have recently identified human liver cell lines that endogenously express ACE2 giving us a unique opportunity to investigate the function of this enzyme. The aim of the present project is to provide further insights into the role of ACE2 in liver disease by determining the regulation, location and transport of ACE2 in cultured liver cells as well as in rat models of liver injury.Read moreRead less
Hepatocyte Replicative Arrest, Hepatic Progenitor Cells And The Ductular Reaction In Hepatic Fibrogenesis
Funder
National Health and Medical Research Council
Funding Amount
$527,683.00
Summary
Chronic liver diseases such as hepatitis C and obesity-related fatty liver can be associated with scarring that eventually results in cirrhosis and liver failure. We are unsure why this scarring occurs, but as hepatitis and fatty liver are becoming more common it is necessary to understand this process so that effective therapies can be developed. This study looks at one possible mechanism to explain the development of liver scarring. We believe that the normal repair mechanisms of the liver lea ....Chronic liver diseases such as hepatitis C and obesity-related fatty liver can be associated with scarring that eventually results in cirrhosis and liver failure. We are unsure why this scarring occurs, but as hepatitis and fatty liver are becoming more common it is necessary to understand this process so that effective therapies can be developed. This study looks at one possible mechanism to explain the development of liver scarring. We believe that the normal repair mechanisms of the liver lead to the production of liver cells to replace those that have died, but in some circumstances also produce small bile ducts that drain bile from the hepatocytes. These small bile ducts may have a previously unsuspected role in stimulating the scar formation. The study will see if the small bile ducts are produced in a range of liver diseases in humans, and will use rodent models to find the factors responsible for stimulating the scarring. When the process is understood more clearly, it could lead to the development of new or more effective therapies to reduce or even reverse liver scarring.Read moreRead less
Host Determinants Of Hepatitis C-associated Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$610,376.00
Summary
Hepatitis C virus (HCV) infection is a major cause of liver disease and associated deaths in Australia. HCV infection leads to progressive liver failure and may be associated with the development of liver cancer. Currently there are an estimated 220,000 people in Australia living with HCV infection, and by 2020 it is estimated that this number will treble. There is now considerable evidence to indicate that the effect of HCV on the liver is due to ongoing immune activity and the build up of fat ....Hepatitis C virus (HCV) infection is a major cause of liver disease and associated deaths in Australia. HCV infection leads to progressive liver failure and may be associated with the development of liver cancer. Currently there are an estimated 220,000 people in Australia living with HCV infection, and by 2020 it is estimated that this number will treble. There is now considerable evidence to indicate that the effect of HCV on the liver is due to ongoing immune activity and the build up of fat (steatosis) in the liver. This results in the production of biochemical products that lead to tissue damage and to eventual destruction of the liver. Further evidence has recently emerged to suggest that the susceptibility to, and outcome of HCV infection may be influenced by genetic variation in the infected population. The chief investigators on this project have established the best characterised clinical cohort of HCV infected persons worldwide. Further, they have developed considerable expertise in the field of genetics, i.e. the analysis of genes that influence the host's response to an illness. Using this information and expertise, we propose in the present study to analyse in detail the host genetic factors that contribute to variations in the response to HCV, and its correlation with HCV-associated liver damage. This data could allow the development of better patient care strategies and the design of novel therapeutics.Read moreRead less
Role Of Tryptophan Metabolism In Liver Transplant Tolerance And Rejection
Funder
National Health and Medical Research Council
Funding Amount
$401,203.00
Summary
Many thousands of Australians have a failing liver and the only treatment for this is a liver transplant. Liver transplantation is a major life-saving strategy and hundreds of Australians are rescued each year who would otherwise have died. Rejection of the transplant is the major problem affecting these patients. This project investigates an animal model where a transplanted rat liver is not rejected, even though the recipient receives no treatment. Previous studies from our group have shown th ....Many thousands of Australians have a failing liver and the only treatment for this is a liver transplant. Liver transplantation is a major life-saving strategy and hundreds of Australians are rescued each year who would otherwise have died. Rejection of the transplant is the major problem affecting these patients. This project investigates an animal model where a transplanted rat liver is not rejected, even though the recipient receives no treatment. Previous studies from our group have shown that acceptance is due to donor white blood cells transferred with the liver and based on this finding we are developing treatments that can be used in transplant patients. The current application for funding tests another breakthrough that we have recently made, that treatment of the recipient with a substance called 1-methyltryptophan prevents liver acceptance. 1-methyltryptophan prevents the activity of an enzyme called indoleamine dioxygenase, which we have shown to be increased in liver recipients that accept their graft. This is strong evidence that indoleamine dioxygenase is involved in liver transplant tolerance. These findings show that liver acceptance should be improved by increasing the levels of indoleamine dioxygenase at the time of transplantation. The aim of the current application is to examine whether increased levels of indoleamine dioxygenase expression in the transplanted liver can lead to an improved outcome. We will use two novel techniques to increase expression: gene therapy or treatment of the donor with IL-4. For gene therapy, an expression system will be used that we have recently shown is specific for the liver. In current NHMRC-funded experiments we have shown that IL-4 treatment of donor liver leads to marked increases in indoleamine dioxygenase expression. Ultimately it is intended that these findings will be used to prolong the survival of liver transplant patients by revealing new ways to prevent rejection of liver transplants.Read moreRead less