MERTK Receptor Tyrosine Kinase: A Novel Therapeutic Target For Liver Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$870,972.00
Summary
Hepatic fibrosis is the principal cause of liver-related morbidity and mortality, for which there are no effective therapies. Thus, there is an urgent and unmet need to identify new targets to treat liver fibrosis. We have demonstrated for the first time, that liver fibrosis correlates with elevated hepatic expression of MERTK, a receptor tyrosine kinase. This project will explore whether MERTK function can be exploited to target and reverse liver fibrosis
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
Iron Metabolism And The Cirrhotic Liver:studies On Iron Absorption And Hepatic Iron Kinetics
Funder
National Health and Medical Research Council
Funding Amount
$256,980.00
Summary
Patients with liver disease awaiting liver transplantation often have excess iron in the liver that aggravates the existing liver disease. We have shown that patients with cholestatic liver disease, (due to poor bile excretion), do not have much iron in the liver compared to those patients with hepatocellular cirrhosis, (where the liver cells are damaged). Why this is so is unknown. Iron is normally absorbed from the diet by with the help of special molecules in the small intestine, carried in t ....Patients with liver disease awaiting liver transplantation often have excess iron in the liver that aggravates the existing liver disease. We have shown that patients with cholestatic liver disease, (due to poor bile excretion), do not have much iron in the liver compared to those patients with hepatocellular cirrhosis, (where the liver cells are damaged). Why this is so is unknown. Iron is normally absorbed from the diet by with the help of special molecules in the small intestine, carried in the blood to the liver where it is used by the cells. We would like to study how the proteins that transport iron in the intestine function and see if this is a different in disease. We would also like to examine exactly which molecules are important in depositing iron in the liver in patients with cirrhosis. We will work on animal models of liver disease as well as humans. We will treat animals so that they have liver disease that resembles human subjects with cirrhosis. These treatments include (1) feeding the animals carbon-tetrachloride, a toxin which damages the liver cells and therefore causes hepatocellular liver injury, and (2) tying the bile duct which stops the flow of bile and this results in cholestatic liver injury. It is known which proteins takes iron into the normal liver cells but no one knows which molecules transport the iron in liver disease. We think they may be different, because when the liver becomes diseased, scarring occurs this results in cirrhosis. Molecules that could easily enter liver cells may now be too big to pass through the openings. These studies are important since they will suggest new treatments to patients with liver disease who are awaiting a liver transplant and the treatment will probably differ depending on which type of liver disease the patient has.Read moreRead less
Nutrition, Physical Function And Muscle Mass In Advanced Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$303,014.00
Summary
Muscle wasting is associated with increased risk of death in patients with liver disease. Many factors contribute to this muscle wasting, but our group’s recent finding that testosterone therapy increases muscle mass in men with liver disease remains the only proven treatment. This project aims to increase understanding of the causes of muscle wasting and to show that testosterone treatment improves clinical outcomes, which could improve the health of liver disease sufferers worldwide.
A Whole Genome Association Study For Determinants Of Clinical Outcome And Treatment Response In Chronic Hepatitis C
Funder
National Health and Medical Research Council
Funding Amount
$360,133.00
Summary
Chronic hepatitis C infection (CHC) causes liver failure, liver cancer and death. The treatment response rate is poor. Understanding of the factors that increase an individual’s risk of developing serious liver disease, or that lead to treatment failure, is limited. This project, the first of its kind, will involve screening 1600 CHC patients for genes that are associated with disease outcome and treatment response, to identify novel targets for drug and vaccine development
Centre For Clinical Research Excellence To Improve Outcomes In Chronic Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$2,000,000.00
Summary
This Centre will provide new information to improve clinical outcomes for people with chronic liver disease. Among people referred by GPs with abnormal liver tests, two thirds have hepatitis C or non-alcoholic steatohepatitis. The Centre aims to develop non-invasive ways to identify those with progressive liver disease, and will assess whether lifestyle adjustments (diet and exercise) improve liver injury and fibrosis progression. They hope to improve the health and survival of people with advan ....This Centre will provide new information to improve clinical outcomes for people with chronic liver disease. Among people referred by GPs with abnormal liver tests, two thirds have hepatitis C or non-alcoholic steatohepatitis. The Centre aims to develop non-invasive ways to identify those with progressive liver disease, and will assess whether lifestyle adjustments (diet and exercise) improve liver injury and fibrosis progression. They hope to improve the health and survival of people with advanced stage cirrhosis who are waiting for a liver transplant by correcting nutritional problems, osteoporosis and earlier detection and treatment of liver cancer. The program forms the basis for clinical research training for GPs, specialists, nurses, dieticians, sports medicine and other health care professionals.Read moreRead less