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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
The Role Of The Adiponectin Receptors In Liver Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$393,159.00
Summary
Advanced liver scarring (fibrosis) contributes to the death of 1500 Australians annually. Two-thirds of our community is overweight or obese, and this worsens liver disease. A protein secreted by fat, adiponectin, may be important as it acts on liver cells to promote fibrosis. To understand adiponectins role, we will use mice null for adiponectin receptor genes and study its action on liver cells. This study will improve our understanding of liver scarring biology and patient treatments.
Mechanisms Of Hepatic Fibrogenesis In Chronic Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$697,209.00
Summary
Despite advances made in understanding the mechanisms of liver injury, chronic liver disease continues to be one of the most rapidly growing causes of death in subjects aged <65 years. This is the result of uncontrolled wound healing and regeneration leading ultimately to cirrhosis and liver cancer. This research will identify and characterise pathways that control the wound healing response to liver injury, involving the processes of inflammation, scarring and restitution of normal liver mas ....Despite advances made in understanding the mechanisms of liver injury, chronic liver disease continues to be one of the most rapidly growing causes of death in subjects aged <65 years. This is the result of uncontrolled wound healing and regeneration leading ultimately to cirrhosis and liver cancer. This research will identify and characterise pathways that control the wound healing response to liver injury, involving the processes of inflammation, scarring and restitution of normal liver mass.Read moreRead less
THE ROLE OF THE HEPATOCYTE HEDGEHOG PATHWAY IN PROGRESSIVE LIVER INJURY
Funder
National Health and Medical Research Council
Funding Amount
$570,876.00
Summary
This research plan investigates the role of a pathway, known as the Hedgehog pathway, in the development of liver disease which can result in end-stage scarring known as cirrhosis and even lead to liver cancer (known as Hepatocellular carcinoma). Hepatocellular carcinoma is the globally the third most common cause of cancer death and our research will help to better understand how liver injury develops and how this then leads to liver cancer.
Inflammatory Pathways To Liver Fibrosis In Non-alcoholic And Alcoholic Steatohepatitis: Reversal By NLRP3 Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$572,857.00
Summary
Nonalcoholic steatohepatitis (NASH) caused by obesity and diabetes made worse by alcohol, leads to cirrhosis. There is no effective treatment. In mice with NASH, MCC950, a novel drug that blocks NLRP3 (molecule that incites inflammation) reverses liver inflammation and possibly scarring. This proposal will test what activates NLRP3 in NASH, and whether blocking it completely with MCC950 or a new lasting longer inhibitor will dissolve severe liver scarring, and scarring made worse by alcohol.
Upper Gastrointestinal Motility And Glycaemic Control In Diabetes Mellitus
Funder
National Health and Medical Research Council
Funding Amount
$543,301.00
Summary
The application of novel techniques to evaluate gastrointestinal motor function has established that the rate at which the stomach empties is abnormally slow in ~50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying, which was thought to be an infrequent complication of diabetes, may contribute to a number of problems including symptoms such as nausea and bloating, and poor control of blood glucose concentrations. The blood glucose ....The application of novel techniques to evaluate gastrointestinal motor function has established that the rate at which the stomach empties is abnormally slow in ~50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying, which was thought to be an infrequent complication of diabetes, may contribute to a number of problems including symptoms such as nausea and bloating, and poor control of blood glucose concentrations. The blood glucose level itself also has a reversible effect on both stomach contractions and symptoms; when the blood glucose is abnormally high, the rate at which the stomach empties is slower, and symptoms, such as fullness, are greater. The rate of stomach emptying and the absorption of sugar from the intestine have a major influence on the rise in the blood glucose level after a meal. This is important because in people with diabetes it is desirable to maintain blood glucose levels as close as possible to normal to minimise the risk of complications such as eye and nerve damage. Specific modifications in diet and recently developed drugs which have actions similar to that of the hormone, glucagon-like peptide-1, may improve blood glucose control in type 2 diabetes by slowing the rate of gastric emptying. People with cystic fibrosis frequently develop diabetes which is often difficult to manage; this may result from abnormally rapid gastric emptying and impaired release of hormones. If so, pancreatic enzyme replacement, in the form of tablets, should prove effective. Our group has conducted research in this area for about 24 years and have performed the most comprehensive studies to date resulting in international recognition. The studies proposed in the current application represent a logical development from our previous work and have important implications for the management of diabetes.Read moreRead less
Defining The Role Of MMP-9-expressing Macrophages In Liver Injury In Chronic Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$542,028.00
Summary
Defining pathways that lead to fibrosis in chronic liver disease is an urgent priority and unmet need because cirrhosis remains a major cause of death. We will study the development of an additional fibrogenic pathway involving altered liver repair mechanisms, in order to seek ways to restore liver function. New insights arising from this novel research could significantly advance our understanding of how fibrosis develops and lead to new approaches to treat and prevent advanced liver disease.
Role Of Human Amnion Epithelial Cells In Resolving Hepatic Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$618,755.00
Summary
When the liver is injured repeatedly by viruses and alcohol, it responds through a wound healing process that can lead to extensive scar tissue in the liver (cirrhosis). This condition may require liver transplantation and lifelong use of drugs to prevent the body from rejecting the new organ. To develop an alternate therapy, we will study if substances secreted by amnion cells from the human placenta (afterbirth), which would normally be discarded, can reduce liver scar tissue in mice .
Tissue Ferritin Is A Damage-associated Molecular Pattern (DAMP) In Inflammasome-induced Inflammation Associated With Hepatic Stellate Cell Activation And Fibrogenesis In Chronic Liver Disease.
Funder
National Health and Medical Research Council
Funding Amount
$783,612.00
Summary
We have generated considerable evidence for a role for tissue ferritin as a mediator of inflammation associated with liver fibrosis (scarring) These highly novel and innovative studies will assist in identifying pathways involved in the proinflammatory phenotype of hepatic stellate cells (scar-forming cells in the liver) in chronic liver disease and thus will greatly aid in understanding how liver scarring occurs in chronic liver disease.