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
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
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
Role Of Nuclear Receptors In Hepatic Injury And Fibrogenesis
Funder
National Health and Medical Research Council
Funding Amount
$443,520.00
Summary
Chronic liver disease is a major cause of death and ill health on a word-wide scale. Several common liver diseases, such as hepatitis B, hepatitis C and non-alcoholic steatohepatitis (fatty liver disease not due to alcohol), are capable of causing protracted liver damage. Irrespective of the cause of injury, the liver has a very narrow way of responding to chronic damage. The most important and insidious of these is hepatic fibrosis (scarring), which, along with liver regeneration, eventually le ....Chronic liver disease is a major cause of death and ill health on a word-wide scale. Several common liver diseases, such as hepatitis B, hepatitis C and non-alcoholic steatohepatitis (fatty liver disease not due to alcohol), are capable of causing protracted liver damage. Irrespective of the cause of injury, the liver has a very narrow way of responding to chronic damage. The most important and insidious of these is hepatic fibrosis (scarring), which, along with liver regeneration, eventually leads to cirrhosis if the injurious process is sufficiently intense and sustained. Liver cirrhosis is the precursor to several undesirable complications of liver disease, most notably primary liver cancer (also called hepatoma), liver failure and severe bleeding from the gut. Therefore, it is not surprising that effective strategies to control liver injury and prevent cirrhosis have been called the holy grail of liver research. To date the only therapies for substantially improving the outcome of patients with chronic liver disease are those that halt or remove the cause of injury. Unfortunately, in many cases it is still not possible to remove or effectively treat the cause of injury. Because of this there is intense interest in therapies that might favourably alter the response of the liver to injury and especially in those that may retard or inhibit scarring and prevent cirrhosis. Nuclear receptors are sensors that control many aspects of the body's metabolism, especially the metabolism of cholesterol and fat. Recently, our work and that of others has suggested that some nuclear receptors may play a vital role in how the liver responds to damage and whether the liver will the scar and move on to cirrhosis. Our experiments will determine if this is so, and which of the several nuclear receptors likely to be involved are the important ones. We will then extend these studies to see if drugs that activate these receptors will improve or prevent severe liver disease.Read moreRead less