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
MECHANISMS OF DISORDERED HEPATIC LIPID PARTITIONING IN NON-ALCOHOLIC STEATOHEPATITIS
Funder
National Health and Medical Research Council
Funding Amount
$449,591.00
Summary
Fatty liver is the commonest form of liver disease. It is strongly associated with obesity and maturity onset diabetes. The majority of cases of fatty liver disease cause no complications, but when inflammation and liver damage also occur, in the condition of non-alcoholic steatohepatitis or NASH, liver scarring and eventually cirrhosis or liver cancer can result. The reason why some people with fatty liver disease develop NASH and others do not (benign or simple steatosis) is unknown and is the ....Fatty liver is the commonest form of liver disease. It is strongly associated with obesity and maturity onset diabetes. The majority of cases of fatty liver disease cause no complications, but when inflammation and liver damage also occur, in the condition of non-alcoholic steatohepatitis or NASH, liver scarring and eventually cirrhosis or liver cancer can result. The reason why some people with fatty liver disease develop NASH and others do not (benign or simple steatosis) is unknown and is the subject of this research. The studies will be performed in a novel mouse model of obesity and diabetes, the fat aussie mouse, in which all animals develop fatty liver disease after a few months. When fat aussie mice are fed a Macdonald's diet [high in saturated fat] they develop full-blown NASH with liver scarring. Before NASH develops in fat aussie mice, blood levels of adiponectin (a protein produced from fat storage cells) fall. Together with high blood insulin and high blood sugar levels, it is proposed that these changes are what leads to an extraordinarily high build up of fat (lipid) molecules in the liver, to the extent that the fat ultimately damages the liver in a process called lipotoxicity. The planned research will first test whether this hypothesis is correct, and then set about ways to prevent or reverse such a dangerous build up of fats in the liver. Strategies include a high olive oil diet (which is protective in another model of steatohepatitis), correction of blood adiponectin levels, lowering of insulin and blood sugar levels. The anticipated results are a much better understanding of how complications come about in fatty liver disease, and therefore insights into how this disorder can be prevented or reversed in those who are predisposed.Read moreRead less
DNA Repair Mechanisms In The Pathogenesis Of Hepatocellular Carcinoma
Funder
National Health and Medical Research Council
Funding Amount
$339,078.00
Summary
Hepatocellular carcinoma (HCC) or cancer originating in the liver ranks 5th in worldwide frequency among tumours, and is the 3rd highest cause of cancer in our region. The incidence is increasing in most countries including Australia, Japan and USA. The overall prognosis is poor, with >80% affected persons dying from this disorder. The risk factors for HCC are well known and include chronic hepatitis B or C virus infection, alcoholism and liver iron accumulation. Despite the vast amount of in ....Hepatocellular carcinoma (HCC) or cancer originating in the liver ranks 5th in worldwide frequency among tumours, and is the 3rd highest cause of cancer in our region. The incidence is increasing in most countries including Australia, Japan and USA. The overall prognosis is poor, with >80% affected persons dying from this disorder. The risk factors for HCC are well known and include chronic hepatitis B or C virus infection, alcoholism and liver iron accumulation. Despite the vast amount of information available regarding these risk factors, the way in which they alter normal liver cells to make them cancerous remains undefined. The majority of liver cancers, regardless of cause, develop in severely scarred, or cirrhotic liver in the presence of chronic liver inflammation. Such an environment causes liver cells, which are usually stable and not dividing, to continue replicating in response to injury; such continued cell division can lead to damaged genetic information in the DNA of these cells. Many cancers are associated with chromosomal damage, including broken ends and deleted genetic material. The main focus of this project to investigate how defective repair of disrupted genetic information contained in DNA of chromosomes in damaged liver cells contributes to the development of liver cancer. Using mice lacking specific genetic information to repair DNA double strand breaks, we plan to investigate whether abnormalities in DNA repair mechanisms in liver cells damaged by diethylnitrosamine (DEN) predisposes liver cells to regenerate abnormally thereby progressing to cancer. We have clues that 7 specific sites in chromosomes where loss of key genes may promote HCC formation. These studies will greatly enhance our understanding of the molecular basis by which HCC develops. The ultimate goal of this research is to develop effective screening and treatment strategies to prevent or interrupt the process of liver cancer development in at-risk individuals.Read moreRead less
Immune Therapies For Chronic Hepatitis B Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$359,085.00
Summary
Hepatitis B virus (HBV) causes acute and chronic infection leading to severe liver damage in many patients and increased risk of primary liver cancer. Worldwide ~350 million people have chronic HBV infection and, while a HBV vaccine is available that protects against new infections, current antiviral drug treatments for existing infection are largely ineffective. Thus, the aim of our project is to develop new treatments for chronic HBV infection using vaccination approaches. These therapies will ....Hepatitis B virus (HBV) causes acute and chronic infection leading to severe liver damage in many patients and increased risk of primary liver cancer. Worldwide ~350 million people have chronic HBV infection and, while a HBV vaccine is available that protects against new infections, current antiviral drug treatments for existing infection are largely ineffective. Thus, the aim of our project is to develop new treatments for chronic HBV infection using vaccination approaches. These therapies will be tested in ducks infected with the duck hepatitis B virus (DHBV), a model for human HBV infection. In brief, DHBV-infected ducks will be treated with a new antiviral drug, Entecavir (ETV) developed by Bristol-Myers Squibb, which blocks virus replication. To accelerate clearance of infected cells before drug-resistant viruses can emerge, the ducks will also be treated in combination with different novel therapeutic vaccines designed to induce strong humoral and cell mediated immune responses. Based on outcomes in initial experiments, we will adjust the vaccination protocol in ETV-treated ducks to maximize reductions in the levels of DHBV in liver and bloodstream, rates of death and clearance of DHBV-infected hepatocytes. Our ultimate goal is to define a protocol for combination antiviral and vaccination treatments that allows elimination of HBV infection, or that achieves a level of control of infection that eliminates ongoing disease by reducing virus loads to virtually undetectable levels.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
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