The Role Of MBOAT7 In Hepatic Inflammation: Implications For Therapy
Funder
National Health and Medical Research Council
Funding Amount
$848,340.00
Summary
When a fatty liver progresses to develop inflammation, patients are at-risk of liver-related morbidity and death. Currently, there are no effective therapies. From human studies, we have discovered that a lipid modifying enzyme (MBOAT7) profoundly regulates liver inflammation. In this proposal, we will obtain a detailed understanding of how the activity of this pathway modulates inflammation. We expect to show that MBOAT7 is a novel ‘druggable’ pathway for the treatment of liver inflammation.
Understanding The Role Of Sugar Metabolism In Liver Tumour Growth
Funder
National Health and Medical Research Council
Funding Amount
$631,979.00
Summary
Primary liver cancer is a deadly disease with limited chemotherapeutic options. The investigators of this proposal have recently determined that sugar intake (but not fat or complex carbohydrate) is a dominant driver of liver tumour growth in mice. The current proposal will investigate the specific contributions of glucose versus fructose in tumour burden, and determine whether blocking the conversion of sugars to fat in the liver represents a therapeutic strategy to block tumour growth in mice.
Liver Injury And Iron Homeostasis In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$631,370.00
Summary
Iron disorders and liver disease are a significant burden on society, affecting many in the prime of their life. Disordered iron metabolism also plays a significant role in many disorders and diseases including cancers, neurodegenerative and iron overload disorders, and anaemia associated with chronic disease. My objective is to understand the molecules and mechanisms involved, and to develop strategies and reagents to diagnose, prevent and treat liver and iron-related disease.
HFE-associated Steatohepatitis: Mechanisms And Therapies
Funder
National Health and Medical Research Council
Funding Amount
$650,813.00
Summary
Iron and fat alter normal iron metabolism and cause more severe disease in combination. In this study we will study the relationship between liver disease caused by increased body iron and the consumption of excess fat and the causal mechanisms. We will then examine new therapies for the treatment of iron-associated fatty liver disease.
Development Of Novel Therapies To Treat Obesity Related Metabolic Diseases
Funder
National Health and Medical Research Council
Funding Amount
$2,981,372.00
Summary
Obesity results in the development of many diseases particularly as we age. These diseases include type 2 diabetes, fatty liver diasease and dementia. This research rpogram with develop new strategies and therapies targeted to treat these obesity related diseases.
Characterisation Of The Mechanisms Of Gastrointestinal And Hepatic Iron Transport In Hereditary Haemochromatosis
Funder
National Health and Medical Research Council
Funding Amount
$474,750.00
Summary
Hereditary haemochromatosis is a very common genetic disease that affects approximately 1:200 Australians. It alters the way the body uses iron. Iron is essential for health but too much iron is toxic to the body and causes harmful damage to organs. In hereditary haemochromatosis the body absorbs too much iron from the diet and most of the extra iron goes to the liver where it may cause liver cirrhosis and liver cancer. Some of the excess iron also goes to the heart, pancreas and joints where it ....Hereditary haemochromatosis is a very common genetic disease that affects approximately 1:200 Australians. It alters the way the body uses iron. Iron is essential for health but too much iron is toxic to the body and causes harmful damage to organs. In hereditary haemochromatosis the body absorbs too much iron from the diet and most of the extra iron goes to the liver where it may cause liver cirrhosis and liver cancer. Some of the excess iron also goes to the heart, pancreas and joints where it can lead to heart failure, diabetes and arthritis, respectively. There are several types of haemochromatosis that are caused by mutations in different genes that are important in the regulation of iron metabolism. In this study we will investigate two types of haemochromatosis caused by mutations in genes called HFE and transferrin receptor 2. How defects in these genes cause iron overload is not known. We will use laboratory models that have mutations in HFE and transferrin receptor 2 genes to identify for the first time how these proteins control the amount of iron the body absorbs from the diet and how much iron to delivered to the tissues such as the liver. From this study, we will gain a better understanding of the role of HFE and transferrin receptor 2 in both normal iron metabolism and haemochromatosis. This new knowledge will provide opportunities for the development of new more effective therapies for the prevention and treatment of iron overload.Read moreRead less
An Integrated Approach To Identify The Molecular Mechanisms Contributing To The Pathogenesis Of Insulin Resistance: Targeting The Liver And Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$415,218.00
Summary
The inability of muscle and liver to utilise sugar from the blood is a major problem that contributes to the development of obesity and diabetes. How these problems occur is unknown. The goal of my research is to identify what causes the muscle and liver problem, and whether fixing these problems will reduce obesity and diabetes. Since the number of people with obesity and diabetes is predicted to double over the next decade, we need to understand the cause of these diseases.
Repair Of Urea Cycle Defects In Mice By RAAV-mediated Gene Transfer: Towards Gene Therapy For Genetic Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$445,578.00
Summary
Gene therapy has the potential to cure many genetic metabolic liver diseases. The key challenge is the development of gene transfer technologies-strategies with the necessary efficacy and safety. Vectors based on adeno-associated virus (AAV) show special promise for gene transfer to the liver, having been extensively evaluated in small and large animal models. The ongoing challenge is to achieve the higher levels of gene transfer required for human therapy. A recent quantum advance has been the ....Gene therapy has the potential to cure many genetic metabolic liver diseases. The key challenge is the development of gene transfer technologies-strategies with the necessary efficacy and safety. Vectors based on adeno-associated virus (AAV) show special promise for gene transfer to the liver, having been extensively evaluated in small and large animal models. The ongoing challenge is to achieve the higher levels of gene transfer required for human therapy. A recent quantum advance has been the development of improved AAV vectors with dramatically higher gene transfer efficiencies (up to two orders of magnitude in the liver). This places successful liver-directed gene therapy within reach. Initial human studies will only be possible in the context of severe diseases where existing therapies are high risk or inadequate. Accordingly, we have chosen the most common urea cycle defect, OTC deficiency, as a disease model. In its severe form neonatal hyperammonaemia is associated with a high risk of death and significant disability in those who survive the newborn period. Using the spf(ash) mouse model of OTC deficiency we propose to develop gene therapy strategies capable of achieving life-long disease cure. Preliminary data has confirmed feasibility, and suggests that the greater number of cells in the human liver requiring genetic repair will not prove insurmountable. The proposal focuses on issues critical to success in humans. These include strategies to minimise the number of repaired liver cells required for clinical benefit, overcoming the effects of liver growth, investigating the potential impact of OTC mutations on gene therapy, and establishing the likely efficiency of gene transfer in human liver cells and large animal livers equivalent in size to the human neonate. These studies are part of a long-term commitment to progress through to human clinical trials of gene therapy for urea cycle defects. The potential health and economic benefits are immense.Read moreRead less
This research proposal will identify changes in liver-secreted proteins during the development of fatty liver, and in the transition from fatty liver to the more advanced form of liver disease, non-alcoholic steatohepatitis (NASH). Understanding the differences in protein secretion between NASH patients and patients with normal/fatty liver will provide the opportunity to identify disease biomarkers that could be determined from a blood sample. This will provide a major shift in clinical care.