The Effect Of Hepatic Pseudocapillarisation Of Old Age On The Disposition Of Chylomicron Remnants And Chylomicrons
Funder
National Health and Medical Research Council
Funding Amount
$204,750.00
Summary
Old age is the major risk factor for atherosclerosis, and vascular disease secondary to atherosclerosis (eg heart attacks and strokes) is the major cause of death and disability in the Western World. As yet there has not been any clear explanation for why old age itself is a risk factor for atherosclerosis. In this study, we are investigating how changes in the liver in old age predispose to hyperlipidaemia and hence vascular disease. We recently discovered changes in the blood vessels of the li ....Old age is the major risk factor for atherosclerosis, and vascular disease secondary to atherosclerosis (eg heart attacks and strokes) is the major cause of death and disability in the Western World. As yet there has not been any clear explanation for why old age itself is a risk factor for atherosclerosis. In this study, we are investigating how changes in the liver in old age predispose to hyperlipidaemia and hence vascular disease. We recently discovered changes in the blood vessels of the liver that occur with old age that we have called pseudocapillarisation. These changes have profound effects on the transport of many substrates including toxins, drugs, oxygen, hormones and lipids from the blood into the liver and thus may explain in part the fact that old age is the major risk factor for many diseases and adverse drug reactions. In this study we are interested in the transfer of fats called chylomicron remnants from blood into the liver. Chylomicron remnants are lipoproteins rich in triglycerides that are produced after meals and broken down by the liver. In order to be metabolised, chylomicron remnants must pass through pores in the liver blood vessels called fenestrations. In old age, we have found that these fenestrations are reduced substantially, which will impair the uptake of chylomicron remnants by the liver, leading to marked increases in fat in the blood stream after meals. In this study, we will examine the effects of old age on the ability of the liver to metabolise chylomicron remnants, in particular focussing on the effects of the age-related loss of fenestrations on chylomicron remnant uptake. As well as providing an understanding of the crucial link between ageing and atherosclerosis, the studies will provide a potential new therapeutic target for the prevention of atherosclerosis in older people.Read moreRead less
MECHANISTIC ROLE OF CHOLESTEROL IN NON-ALCOHOLIC STEATOHEPATITIS
Funder
National Health and Medical Research Council
Funding Amount
$533,541.00
Summary
Fatty liver is present in 15-30% of Australians, related to obesity, diabetes and heart attack. Two-thirds of cases reverse easily. The remainder evolve to non-alcoholic steatohepatitis (NASH), liver damage that can lead to cirrhosis and liver failure. This research seeks to find out why some cases of fatty liver lead to NASH, and whether cholesterol that accumulates in the livers of mice with NASH is what causes that damage. If so, we will find new ways to treat NASH by diet or drugs.
Cholestasis And Hepatocyte Injury In Chronic Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$615,967.00
Summary
The aim of this project is to understand the consequences of long-term cholestasis or impaired bile excretion/flow on normal liver cells (hepatocytes) and to test whether specific bile acids can cause irreversible damage to hepatocytes leading to their transformation into pre-malignant cells and hepatocellular carcinoma (primary liver cancer). The results from this project will inform new strategies in screening, prevention and treatment of liver cancer in children and adults with cholestasis.
Significance Of Microparticles In The Pathogenesis Of Liver Ischemia Reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$643,958.00
Summary
The overall aim of the project is to investigate the significance of microparticles in liver ischemia reperfusion injury (IRI). IRI causes damage to donor livers stored in preparation for liver transplantation. We postulate that microparticles released from the liver are critical in this form of injury. The expected outcomes are novel insights into liver IRI with the aim of developing new approaches to prevent liver damage during liver surgery, transplantation and shock.
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.
P53 And Hepatocyte Proliferation In Chronic Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$331,360.00
Summary
The aim of this project is understand how loss of control of p53, a tumour suppressor gene, in liver cells causes the transformation of normal liver cell (hepatocyte) to ‘rouge’ pre-cancerous cells in hepatocellular carcinoma (HCC) or primary liver cancer. We will test novel therapies to restore p53 function in liver cells in order to prevent or retard the development of HCC in patients with cirrhosis and those ‘at risk’ of this rapidly increasing fatal cancer in Australia.
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
The Role Of The Hepatocyte And EMMPRIN In Liver Injury
Funder
National Health and Medical Research Council
Funding Amount
$607,487.00
Summary
This research plan investigates the role of the hepatocyte, the principal functional cell within the liver in the development of liver disease. Liver injury can result in end-stage scaring known as cirrhosis as well as leading to liver cancer. Our research aims to identify strategies for reversing the fibrotic process and result damage to the liver
Protecting Fatty Livers From Hepatic Ischemia-reperfusion Injury In Liver Surgery And Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$624,960.00
Summary
About one third of the population have a fatty liver, and this greatly increases risks of liver failure after liver surgery or when fatty donor livers are used for transplantation (such organs are currently disposed of). The disease process is called ischemia-reperfusion injury (IRI). The investigators have recently shown that both fibrates and statins provide partial protection against IRI in fatty livers. This research is directed at establish the protective mechanisms, and whether combination ....About one third of the population have a fatty liver, and this greatly increases risks of liver failure after liver surgery or when fatty donor livers are used for transplantation (such organs are currently disposed of). The disease process is called ischemia-reperfusion injury (IRI). The investigators have recently shown that both fibrates and statins provide partial protection against IRI in fatty livers. This research is directed at establish the protective mechanisms, and whether combination drugs are more effective.Read moreRead less
Manganese is an essential trace element for normal health. However in some medical conditions manganese can build up in the brain and cause a Parkinson's like disease called manganism. Experimental evidence suggests that the liver plays an important role in the development of manganism and this project aims to explore the way the liver handles manganese in health and disease. These studies may assist in understanding how manganism develops.