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.
The Role Of Steatosis In Promoting Cellular Injury And Fibrogenesis In Human Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$414,375.00
Summary
Lay Description Fatty liver (steatosis) is important because it increases the vulnerability of the liver to factors that trigger inflammation and fibrosis. Patients with steatosis may develop steatohepatitis spontaneously and this increases the risk and rate of progression to cirrhosis, with consequent liver-related morbidity and mortality. In addition, steatosis significantly potentiates the severity of liver damage that is caused by other agents such as drugs or infections. To improve the prog ....Lay Description Fatty liver (steatosis) is important because it increases the vulnerability of the liver to factors that trigger inflammation and fibrosis. Patients with steatosis may develop steatohepatitis spontaneously and this increases the risk and rate of progression to cirrhosis, with consequent liver-related morbidity and mortality. In addition, steatosis significantly potentiates the severity of liver damage that is caused by other agents such as drugs or infections. To improve the prognosis of patients with fatty livers, it is important to understand why hepatic steatosis increases the risk for more serious liver disease. To date, much of our understanding of mechanisms of liver injury in fatty liver disease comes from animal models, and these findings have not been systematically evaluated in the human disease. Apart from optimizing body weight, there is no established treatment of fatty liver disease. Delineation of the mechanisms involved in liver injury will allow the development of specific protective strategies for steatotic livers.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.
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
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.
Monocytes/macrophages In Chronic Liver Diseases: Cross-talk With Hepatocytes And Nonparenchymal Cells And Role In Progressive Liver Injury
Funder
National Health and Medical Research Council
Funding Amount
$598,645.00
Summary
More than 170 million people world-wide are chronically infected with the hepatitis C virus. Approximately 10-15% of chronically infected subjects develop cirrhosis with its attendant risks of liver failure and hepatocellular carcinoma. The objective of this important project is to examine the mechanisms by which monocytes and macrophages (cells of the immune system) enhance or impair the progression of liver disease and response to antiviral treatment in patients with chronic hepatitis C.
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.
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
THE ROLE OF THE HEPATOCYTE IN EXTRACELLULAR MATRIX INTERACTIONS IN LIVER FIBROGENESIS
Funder
National Health and Medical Research Council
Funding Amount
$540,438.00
Summary
This study focuses on the main cell within the liver, the hepatocyte, and its role in the development of liver fibrosis. Liver fibrosis arising from liver injury has a common progression characterised by loss of liver structure and the development of dense fibrous bands of tissue in the condition known as cirrhosis. The importance of the outlined research plan is that for the first time the hepatocyte has been identified as having a significant role in the development of liver fibrosis.
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 .