Does Immunosuppression Affect The Post-transplantation Hepatic Fibrogenic Response?
Funder
National Health and Medical Research Council
Funding Amount
$360,000.00
Summary
Liver transplantation is often the only treatment option for patients who progress to end-stage liver disease after initial treatment has failed. Unfortunately, re-emergence of disease is common and patients often develop fibrosis and cirrhosis (scarring of the liver) in the donor organ. In some cases it has been observed that this scarring often develops rapidly, sometimes in a year or less following transplantation. Re-transplantation is often required. This differs from the usual progression ....Liver transplantation is often the only treatment option for patients who progress to end-stage liver disease after initial treatment has failed. Unfortunately, re-emergence of disease is common and patients often develop fibrosis and cirrhosis (scarring of the liver) in the donor organ. In some cases it has been observed that this scarring often develops rapidly, sometimes in a year or less following transplantation. Re-transplantation is often required. This differs from the usual progression of cirrhosis pre-transplant which often takes years or decades to develop. While essential to prevent rejection of the transplanted organ, immunosuppression is not without side effects. To date, few studies have examined the effect of immunosuppressive agents on the development of hepatic fibrosis and the key fibrosis effector cell type, the hepatic stellate cell. These reports have shown that one of the most commonly used immunosuppressant agents (FK-506) may adversely influence fibrosis progression while rapamycin may prevent fibrosis progression. However little is known regarding the mechanisms through which this occurs. We propose to examine the effect of four different immunosuppressants on fibrosis development both in vitro and in vivo to determine whether scar development or scar breakdown pathways are altered post-immunosuppression. If the factors driving the fibrogenesis in the transplanted organ can be elucidated it may then be possible to develop therapeutic strategies to tackle the problem. This may result in a reduced need for re-transplantation which has obvious benefits to the transplant patient but would also reduce the numbers of donor organs required.Read moreRead less
The Alternate Renin Angiotensin System; A Novel Target For The Prevention And Treatment Of Liver Fibrosis And Portal Hypertension
Funder
National Health and Medical Research Council
Funding Amount
$693,950.00
Summary
Cirrhosis of the liver due to chronic hepatitis and other common liver diseases is now a major cause of illness and death in Australia. This project will examine how a hormone system called the renin angiotensin system contributes to the development of liver damage in these diseases. We will study whether drugs targeting this system can be used to reduce liver scarring and prevent the development of cirrhosis and its complications.
Identification Of The Mechanisms Of Hepatic Fibrogenesis Aid In The Detection And Prediction Of Clinical Outcomes In Paediatric Cholestatic Liver Disease.
Funder
National Health and Medical Research Council
Funding Amount
$624,429.00
Summary
Biliary Atresia (BA) and Cystic Fibrosis Liver Disease (CFLD) are important causes of childhood cirrhosis. Diagnosis is difficult, treatments problematic, and outcomes suboptimal. In BA, bile duct obstruction in infants rapidly progresses to liver failure. It is the most common indication for liver transplantation in children. CFLD causes significant morbidity/mortality in about 20% of CF children. This proposal investigates the mechanisms of liver fibrosis (scarring) and the role of fibrosis in ....Biliary Atresia (BA) and Cystic Fibrosis Liver Disease (CFLD) are important causes of childhood cirrhosis. Diagnosis is difficult, treatments problematic, and outcomes suboptimal. In BA, bile duct obstruction in infants rapidly progresses to liver failure. It is the most common indication for liver transplantation in children. CFLD causes significant morbidity/mortality in about 20% of CF children. This proposal investigates the mechanisms of liver fibrosis (scarring) and the role of fibrosis in both diagnosis and predicting clinical outcome.Read moreRead less
HLA-G/H2-Bl Is Critical For Regulating Inflammation In The Liver
Funder
National Health and Medical Research Council
Funding Amount
$494,050.00
Summary
The key factor to induction of liver fibrosis, progression to cirrhosis, and hepatocellular carcinoma is inflammation. Liver transplant and liver regeneration following liver resection are also dramatically impaired by elevation of inflammation. We have identified a potent anti-inflammatory protein, HLA-G, that is critical for regulating post-surgical inflammation in the liver. We will determine if HLA-G can reverse and/or block liver fibrosis and modify HLA-G for improved clinical potential.
Targeting The Pathophysiology And Therapy Of Liver Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$484,006.00
Summary
Hepatic fibrosis, or scarring of the liver, is a serious condition which can lead to liver cancer or death. Treatment of liver scarring is currently not effective once the scarring is well developed. This project aims to examine agents which may act to halt liver scarring once it has already developed. Outcomes from this project may help provide potential treatments to reduce the need for liver transplantation or to reduce patient deaths.
Application Of Follistatin To The Resolution Of Liver Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$330,990.00
Summary
Liver fibrosis or scarring is a consequence of a number of diseases, leading eventually to extensive damage known as cirrhosis. It is a significant health problem both here in Australia and overseas with around 180,000 patients diagnosed each year in the Western world. Cirrhosis arises from many causes, two major groups being patients who contract hepatitis and alcoholics. People with cirrhosis have a much increased risk of liver failure, which requires liver transplantation, or of developing li ....Liver fibrosis or scarring is a consequence of a number of diseases, leading eventually to extensive damage known as cirrhosis. It is a significant health problem both here in Australia and overseas with around 180,000 patients diagnosed each year in the Western world. Cirrhosis arises from many causes, two major groups being patients who contract hepatitis and alcoholics. People with cirrhosis have a much increased risk of liver failure, which requires liver transplantation, or of developing liver cancer, for which current treatments have limited success. We have been studying two proteins, activin and follistatin, both of which are made in the liver. We are interested in activin because it is one of the body's mechanisms to control cell growth, and also seems to stimulate the development of scar tissue. Follistatin is the natural inhibitory substance for activin. It blocks the effects of activin and helps promote cell growth in the liver. We believe that follistatin may also be useful in controlling liver scarring. This process will be studied in animal models of cirrhosis, in the hope that follistatin treatment will reduce the level of liver damage. If successful, this would be important information that would enable us to design treatments applicable to human sufferers of these liver diseases. In another part of the project, we will assess whether activin and follistatin might be useful markers of liver disease. Most patients require a liver biopsy to assess the amount of liver damage, and a simple blood test would be a far easier, less traumatic and cheaper alternative.Read moreRead less
The AGE/RAGE Pathway In Chronic Liver Disease; A Novel Target For Prevention And Treatment
Funder
National Health and Medical Research Council
Funding Amount
$461,822.00
Summary
Cirrhosis of the liver due to non-alcoholic fatty liver disease, chronic hepatitis and other liver diseases is now a major cause of illness and death in Australia. This project will examine how advanced glycation end products (AGEs), compounds formed in the body and also derived from our diet, contributes to the progression of liver scarring in these diseases. We will study whether drugs targeting these compounds can be used to reduce liver scarring and prevent the development of cirrhosis.
Eliminating HCV: Statistical Modelling And Health Economic Evaluation In The New DAA Era
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
While new generation hepatitis C virus (HCV) treatments are highly efficacious, their high cost means multi-pronged approaches will be needed to reach elimination targets. This project will use statistical and mathematical modelling to inform real world health economic evaluations determine the most cost-effective response. This will inform health policy in Australia and globally.