Obesity, Insulin Resistance And Hepatocarcinogenesis: Metabolic Mediators And Molecular Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$199,485.00
Summary
Liver cancer (or hepatocellular carcinoma, HCC) is the 3rd most common cause of cancer death, with the incidence in Australia increasing. Recently, it has been shown that obesity, diabetes and fatty liver disease can lead to HCC; this project will explore how metabolic diseases promote HCC. The role of insulin and fatty acids in promoting DNA damage and cell growth will be examined. Understanding how metabolic disease increases HCC risk will improve prevention strategies and possible treatments.
How Is Lipoprotein Disposition Influenced By Fenestrae In The Hepatic Sinusoidal Endothelium?
Funder
National Health and Medical Research Council
Funding Amount
$310,500.00
Summary
Understanding lipoprotein metabolism is critical for the prevention of vascular disease. The liver is the main site for lipoprotein metabolism. The initial step in the metabolism of lipoproteins by the liver is their transfer across the liver sinusoidal endothelial cells from the blood to the liver cells. Sinusoidal endothelial cells contain pores called fenestrae that are thought to allow direct passage of large substances and thus filter lipoproteins on the basis of size. We propose to fully d ....Understanding lipoprotein metabolism is critical for the prevention of vascular disease. The liver is the main site for lipoprotein metabolism. The initial step in the metabolism of lipoproteins by the liver is their transfer across the liver sinusoidal endothelial cells from the blood to the liver cells. Sinusoidal endothelial cells contain pores called fenestrae that are thought to allow direct passage of large substances and thus filter lipoproteins on the basis of size. We propose to fully define the role of fenestrae in the ultrafiltration of particles such as lipoproteins and microspheres. This will confirm that ultrafiltration by fenestrae in the liver endothelium is an important biological process akin to filtration by the kidney, and relevant for lipoprotein metabolism. We will determine whether oxidative stress, which generates large gaps in the sinusoidal endothelium, increases the transfer of lipoproteins into the liver. This provides a novel mechanism for fatty liver that follows toxic liver injury, and hence, a therapeutic target for this condition. We will determine whether loss of fenestrae induced by the synthetic non-ionic surfactant, pluronic 407, reduces transfer of lipoproteins. This is an entirely novel mechanism and risk factor for hyperlipidaemia. Finally we will investigate lipoprotein (a) which is a potent risk factor for vascular disease. We will assess with lipoprotein (a), through binding other lipoproteins and increasing their size, impedes their transfer through the fenestrations for subsequent hepatic metabolism. From the basic perspective, these studies will prove that fenestrations in the liver endothelial cell are an ultrafiltration system that is significant for lipoprotein metabolism. From the clinical perspective, the studies will generate novel mechanisms for impaired hepatic metabolism of lipoproteins as well as indicating that fenestrae are a potential target for the development of lipid-lowering pharmacotherapies.Read moreRead less
The Role Of TRPM2 Channels In Oxidative Stress-induced Liver Damage
Funder
National Health and Medical Research Council
Funding Amount
$576,265.00
Summary
Oxidative stress plays a central role in liver injury induced by drug toxicity, ischemia-reperfusion, non-alcoholic fatty liver disease and viral hepatitis. A hallmark feature of oxidative-stress mediated hepatocellular death is Ca2+ and Na+ overload which suggest activation of ion channels on the plasma membrane. This project will investigate the role of Transient Receptor Potential Melastatine 2 (TRPM2) non-selective channels in oxidative stress-induced hepatocellular death.
Brain damage resulting from long-term alcohol abuse is localized to discrete regions of the brain and selectively impairs key neuropsychological functions. Alcohol misuse affects processes that control excitability in the brain, leading to the over-stimulation of brain cells. When this continues for long periods the cells are likely to die and most alcoholics misuse alcohol for most of their adult lives. We will study the human brain s capacity to use and respond to glutamate, its major natural ....Brain damage resulting from long-term alcohol abuse is localized to discrete regions of the brain and selectively impairs key neuropsychological functions. Alcohol misuse affects processes that control excitability in the brain, leading to the over-stimulation of brain cells. When this continues for long periods the cells are likely to die and most alcoholics misuse alcohol for most of their adult lives. We will study the human brain s capacity to use and respond to glutamate, its major natural excitant, in the regions that are selectively damaged by alcoholism. How these capacities are affected by heredity, and by diseases commonly associated with alcoholism such as cirrhosis of the liver, will also be explored. If we can understand how selective brain damage occurs in alcoholics we will be better able to devise new drug therapies to combat and prevent it. As well, localized brain damage is a feature of many neurological diseases, so the study will provide a general model of disease mechanisms.Read moreRead less
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