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Role Of Tissue Ferritin As A Proinflammatory Mediator Of Hepatic Stellate Cell Activation In Hepatic Iron Overload.
Funder
National Health and Medical Research Council
Funding Amount
$574,890.00
Summary
The hepatic stellate cell is responsible for liver scarring (fibrosis) in chronic liver diseases such as the iron overload condition Haemochromatosis. Our research has identified a role for tissue-derived ferritin as a proinflammatory cytokine in hepatic stellate cell biology. This proposal will examine the mechanisms associated with ferritin's proinflammatory action and assess its role in the fibrosis which occurs in Haemochromatosis.
Hepatic Fibrogenesis In Paediatric Cholestatic Liver Disease.
Funder
National Health and Medical Research Council
Funding Amount
$254,250.00
Summary
Liver disease in children causes a significant impact on lifespan and quality of life. The commonest causes of liver disease in children are cholestatic, or diseases related to obstruction of bile flow out of the liver. In ways we are only beginning to understand, obstruction of bile flow stimulates liver scar formation which, if untreated, leads to replacement of normal liver tissue and ultimately to failure of the liver. In infants, the most common and serious cholestatic liver disease is bili ....Liver disease in children causes a significant impact on lifespan and quality of life. The commonest causes of liver disease in children are cholestatic, or diseases related to obstruction of bile flow out of the liver. In ways we are only beginning to understand, obstruction of bile flow stimulates liver scar formation which, if untreated, leads to replacement of normal liver tissue and ultimately to failure of the liver. In infants, the most common and serious cholestatic liver disease is biliary atresia. It develops at, or shortly after birth with progressive destruction of the bile ducts, responsible for transporting bile out of the liver. Without early diagnosis and surgery these infants develop progressive liver scarring leading to liver failure and death or liver transplantation within 1-2 years. It is the commonest reason for liver transplantation in children (55-60%) in the Western world. Even with successful surgery, most, if not all patients will come to liver transplantation over the subsequent 25 years because of ongoing, but slower, scar formation. In older children, diseases like cystic fibrosis cause bile duct blockages leading to progressive liver scarring that is slower and unpredictable, contributing to ill health in up to 20% of patients and death from end stage liver disease or liver transplantation in 5%. Using liver tissue from children with these two disorders we have been able to identify the key cells that control the liver scar process, the Hepatic Stellate Cell. We now need to investigate the role of bile constituents on the scar-forming process in these two diseases. We will utilise a well characterised animal model to investigate the influence of bile constituents on cells isolated from this model and apply these findings back to patient samples to determine their role in paediatric cholestatic liver disease. This will help us to better understand the disease process and importantly, develop more effective and earlier treatment.Read moreRead less
Tissue Ferritin Acts As A Proinflammatory Mediator Of Hepatic Fibrosis In Chronic Liver Disease Via Multiple Receptors In Hepatic Stellate Cells Responsible For Both Binding And Signalling.
Funder
National Health and Medical Research Council
Funding Amount
$777,887.00
Summary
Our research has identified a role for tissue-derived ferritin as a proinflammatory cytokine in hepatic stellate cell biology, the cells responsible for liver scarring (fibrosis) in Haemochromatosis. This proposal will identify the receptor responsible for eliciting ferritin's proinflammatory action and assess its role in fibrosis. This study will have implications in chronic liver diseases of varying aetiologies where elevated serum ferrritin is associated with inflammation.
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
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.
Role Of Chemoattractants In Hepatic Stellate Cell Recruitment And Fibrogenesis In Paediatric Cholestatic Liver Disease.
Funder
National Health and Medical Research Council
Funding Amount
$589,175.00
Summary
This project investigates how decreased bile flow in children's liver diseases such as cystic fibrosis and biliary atresia, leads to the release of molecules from the liver which cause recruitment of scar-forming cells. This results in cirrhosis (liver scar) and the necessity for liver transplantation. This project will investigate whether some children are more susceptible to liver scarring due to mutations in genes which cause increased release of these recruitment molecules from the liver.
EXAMINING THE RELATIONSHIP BETWEEN MATRIPTASE-2 AND HEMOJUVELIN, TWO ESSENTIAL REGULATORS OF IRON HOMEOSTASIS
Funder
National Health and Medical Research Council
Funding Amount
$533,541.00
Summary
The control of iron levels is important in health and well being. Too little can lead to iron deficiency and anaemia, conversly too much can lead to haemochromatosis and tissue damage. We will examine the role of two proteins, matriptase-2 and hemojuvelin that when mutated cause iron deficiency or iron overload respectively. We will study how these proteins interact and work in opposite directions to control iron levels. The results will help to develop new therapeutics for iron disorders.
SARA: Delineating Its Association With The Onset And Development Of Liver Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$865,972.00
Summary
Liver disease, a significant burden on society, affects many in the prime of their life. Scarring of the liver is a response to injury due to many factors including alcohol, viruses, obesity, and fatty-liver disease. We have identified a protein associated with liver injury. In this project we will perform a systematic analysis to understand the role of this protein in injury progression. Ultimately we intend to develop tools to prevent and treat liver injury.
Physiologically-based Pharmacokinetics And Pharmacodynamics Of Therapeutic Stem Cells For Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$848,710.00
Summary
This project focuses on the challenging area of effective and optimal dosing cell-based therapy for liver diseases. We will investigate the fate and therapeutic effects of natural, modified and artificial therapeutic cells in the body and in liver regions using a physiologically-based kinetic model. Our key goal is advance cell therapy by providing a better understanding and dosing guidelines.