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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.
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 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.
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.
Novel Interplay Of Oestrogen And Growth Hormone In Regulating Lipid Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$673,045.00
Summary
These studies provide insights into the mechanisms and role of oestrogen in regulating whole body and liver fat metabolism. Oestrogen-related medications that modify the action or tissue availability of oestrogen are widely used therapeutics and can predispose to obesity and fat accumulation in the liver. Whether the effect is direct or through interplay with other metabolic hormones is unknown. This proposal examines their metabolic consequences and impact on obesity and liver health.
The Role Of Endocannabinoids In Chronic Hepatitis C
Funder
National Health and Medical Research Council
Funding Amount
$563,002.00
Summary
Hormones related to cannabis help to regulate fat stores in the human body. CB1 antagonists are a new class of drugs that block these hormones and are being tested for the treatment of obesity and fatty liver. We discovered that Hepatitis C makes the liver more sensitive to these hormones, helping the hepatitis C virus to replicate. This project will determine the mechanisms by which CB1 antagonists prevent hepatitis C virus replication and their potential as a novel therapy for this disease.
IMPAIRED REGULATION OF CYTOCHROMES P450 DURING THE EVOLUTION OF HEPATIC STEATOSIS
Funder
National Health and Medical Research Council
Funding Amount
$186,740.00
Summary
The accumulation of fat in liver is a common problem in early liver injury caused by alcohol, certain drugs and diseases like diabetes. When this occurs the fats can change the amounts of a number of genes and proteins in liver. Cytochrome P450 proteins insert an activated form of oxygen into chemicals, including drugs and fats. In the process, however, some of these activated chemicals can damage surrounding tissues. This project will study the details of how the levels of cytochromes P450 are ....The accumulation of fat in liver is a common problem in early liver injury caused by alcohol, certain drugs and diseases like diabetes. When this occurs the fats can change the amounts of a number of genes and proteins in liver. Cytochrome P450 proteins insert an activated form of oxygen into chemicals, including drugs and fats. In the process, however, some of these activated chemicals can damage surrounding tissues. This project will study the details of how the levels of cytochromes P450 are altered when fat accumulates in liver. The findings may suggest ways in which normal levels of cytochromes P450 can be restored and how to minimise the injurious effects of activated chemicals in liver.Read moreRead less
IC7: A Gp130 Receptor Ligand To Treat Type 2 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$598,833.00
Summary
Over the past decade work from our group has identified that a group of proteins, termed gp130 receptor cytokines, can lead to improvements in both causes and symptoms of type 2 diabetes in both animals and humans. Unfortunately, due to side effects, clinical trial using analogues of these proteins have failed. We believe we know why this is the case and we now have developed new, improved peptides that should overcome these side effects. We hope that we have created a novel drug that will help ....Over the past decade work from our group has identified that a group of proteins, termed gp130 receptor cytokines, can lead to improvements in both causes and symptoms of type 2 diabetes in both animals and humans. Unfortunately, due to side effects, clinical trial using analogues of these proteins have failed. We believe we know why this is the case and we now have developed new, improved peptides that should overcome these side effects. We hope that we have created a novel drug that will help treat type 2 diabetes.Read moreRead less
Factors Controlling Lipid Accumulation In Non-adipose Tissues
Funder
National Health and Medical Research Council
Funding Amount
$463,500.00
Summary
The fat cells of the body are designed to store excess fuel for use when supply from the diet is low, or in situations like exercise, demand is high. Fat also accumulates to some extent in the cells of other tissues types, but in some people the accumulation is excessive. This can have a number of serious effects. In the liver and muscle it can interfere with the ability of insulin to properly regulate the amount of glucose present in the blood, contributing to the development of diabetes. In th ....The fat cells of the body are designed to store excess fuel for use when supply from the diet is low, or in situations like exercise, demand is high. Fat also accumulates to some extent in the cells of other tissues types, but in some people the accumulation is excessive. This can have a number of serious effects. In the liver and muscle it can interfere with the ability of insulin to properly regulate the amount of glucose present in the blood, contributing to the development of diabetes. In the liver, fat accumulation can also lead to cirrhosis and liver failure. Cardiovascular complications, resulting in premature death, are also likely. However despite these devastating consequences it is not clear what the underlying cause of the over-accumulation of fat is not known. In this project we will investigate in detail several aspects of fat metabolism that we think are important in controlling how tissues take up fat from the circulation and whether it is subsequently stored or burnt for energy. We will study the amount of fat that is taken up by different tissues of the body under a range of conditions including fed, and short- and long-term fasting. We will also use drugs to inhibit or promote the amount of fat that is burnt, to see if this changes the rate at which fat is taken up by different tissues. In addition we will accelerate, by genetic manipulation, the rate at which some key enzymes of fat metabolism are produced, to determine their effect on the amount of fat that is stored by different tissue types. Our aim is to determine the metabolic processes that influence fat accumulation in those adversely affected tissues such as liver, heart and skeletal muscle. The identification of the most important processes will contribute significantly to the targeting of therapies aimed at preventing excess fat accumulation and its associated diseases.Read moreRead less