I am a lipid biochemist-cell biologist determining the molecular mechanisms of disorders of lipid metabolism and developing treatments for such disorders. The diseases where lipid metabolism plays a key role include cardiovascular diseases (such as coronary artery disease), metabolic disorders (such as diabetes), some infectious diseases (such as HIV) and neurological disorders (such as Alzheimer disease).
Suppression Of NADPH Oxidase-derived Oxidative Stress By Anti-sense Probes And HDL In Human Vascular Endothelium
Funder
National Health and Medical Research Council
Funding Amount
$455,250.00
Summary
In Australia, coronary heart disease (CHD) causing heart attacks remains the largest cause of death, claiming a staggering 28,000 lives a year. Oxidative stress, resulting from increased production of oxygen free radicals in arteries, is an important cause of CHD, heart attacks and strokes. We seek to understand how such oxyradicals are produced in the key cells that form the lining of all arteries, known as the vascular endothelium. By using novel DNA-type molecules (known as anti-sense) develo ....In Australia, coronary heart disease (CHD) causing heart attacks remains the largest cause of death, claiming a staggering 28,000 lives a year. Oxidative stress, resulting from increased production of oxygen free radicals in arteries, is an important cause of CHD, heart attacks and strokes. We seek to understand how such oxyradicals are produced in the key cells that form the lining of all arteries, known as the vascular endothelium. By using novel DNA-type molecules (known as anti-sense) developed in our laboratory, which block a particular gene causing oxidative stress, we will determine whether this gene is responsible for the formation of oxyradicals in human and mouse cells grown in culture. In addition, we will explore whether this gene is turned on by factors known to be involved in CHD. Finally, we will also investigate whether the good cholesterol known as HDL can act to prevent oxidative stress in human cells, as we discovered it appears to do in living arteries in vivo. If we find it has the same protective effect in endothelium, we will determine how it does this, and which component proteins of the HDL particle are important. This might suggest new treatments to prevent acute events leading to heart attack and stroke, and possibly new applications where damage appears to result from acute oxidative stress, such as in the brain soon after a stroke has occurred. We also have a plan to develop antisense drugs that will target the important gene specifically in the affected endothelium. In addition, we have other specific new drugs that will block this system in arteries. Simultaneously we will be testing the role of this gene in mouse and rabbit models of artery disease, for both our types of drugs might provide valuable new therapeutic agents to target the underlying cause of CHD and not just its symptoms as current drugs do.Read moreRead less
The Role Of Apolipoprotein E In High Density Lipoprotein Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$151,208.00
Summary
Coronary heart disease is a major cause of death and disability in Australia. A high level of blood cholesterol increases the risk of developing coronary heart disease. This increase in coronary risk is caused by the cholesterol that is carried in low density lipoproteins (LDL). However, not all cholesterol is bad. A proportion of the cholesterol in blood is carried high density lipoproteins (HDL), which are powerful protectors against heart disease. People with high blood levels of HDL have a s ....Coronary heart disease is a major cause of death and disability in Australia. A high level of blood cholesterol increases the risk of developing coronary heart disease. This increase in coronary risk is caused by the cholesterol that is carried in low density lipoproteins (LDL). However, not all cholesterol is bad. A proportion of the cholesterol in blood is carried high density lipoproteins (HDL), which are powerful protectors against heart disease. People with high blood levels of HDL have a significantly reduced risk of developing heart disease. HDL consist of several different types of particles that contain lipids (or fats) and proteins. Not all HDL protect equally against coronary heart disease. Our ability to determine which HDL are the most cardioprotective is limited because it is difficult to separate the different types of particles from each other. One thing we do know is that the cardioprotective properties and metabolism of HDL are influenced by the proteins they contain. A considerable amount is known about the effects of the two main HDL proteins on the metabolism and cardioprotective properties of HDL. However, HDL contain several other proteins which are also important in this regard. This project is concerned with one of those other proteins called apolipoprotein E. The evidence that apolipoprotein E protects against heart disease is indisputable. Despite this, almost nothing is known about its role in HDL metabolism. This is because it is difficult to isolate large amounts of apolipoprotein E-containing HDL from plasma. In order to overcome these problems I have developed a novel method for preparing HDL which contain apolipoprotein E. These preparations are comparable to the apoE-containing HDL in human plasma. They will be used in this project to study the influence of apolipoprotein E on HDL metabolism.Read moreRead less
Formation, Structure And Metabolism Of High Density Lipoproteins Containing Both ApoAI And ApoAII On The Same Particle
Funder
National Health and Medical Research Council
Funding Amount
$296,884.00
Summary
It is well known that high levels of cholesterol in blood cause coronary heart disease. It is also known that not all of the cholesterol in blood is bad. Whereas the cholesterol carried in particles called low density lipoproteins (LDLs) causes heart disease, other cholesterol carriers in blood known as high density lipoproteins (HDLs) actually protect against the development of heart disease. However, HDLs include several different populations of particles, only some of which are protective. On ....It is well known that high levels of cholesterol in blood cause coronary heart disease. It is also known that not all of the cholesterol in blood is bad. Whereas the cholesterol carried in particles called low density lipoproteins (LDLs) causes heart disease, other cholesterol carriers in blood known as high density lipoproteins (HDLs) actually protect against the development of heart disease. However, HDLs include several different populations of particles, only some of which are protective. One determinant of the ability of HDLs to protect against coronary heart disease is their protein composition. This project investigates how the protein composition of HDL populations influences their structure, function and metabolism. It is also concerned with understanding what regulates the relative concentrations of the different HDL populations. The studies of HDL structure, function and metabolism will allow us to understand why the different HDL populations differ in their abilities to protect against heart disease. The regulation studies will tell us how to go about designing therapies to increase the levels of those HDL populations that do protect.Read moreRead less
Multifunctional Regualtion Of Angiogenesis By High Density Lipoproteins
Funder
National Health and Medical Research Council
Funding Amount
$480,653.00
Summary
For many sufferers of heart disease and cancer, current treatments do not relieve the debilitating symptoms. The growth of new blood vessels can alleviate the effects of a restricted blood supply, caused by blocked arteries. Conversely, new vessel growth accelerates some diseases such as cancer. HDL is one of the main forms of cholesterol in the blood. Recently we identified a beneficial bifunctional role for HDL in vessel growth. This project will investigate the mechanisms for these effects.
HDL Elevation And Glucose Metabolism: A Mechanistic Proof-of-Concept Intervention Trial In Pre-Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$507,974.00
Summary
This clinical trial will investigate a new treatment strategy for type 2 diabetes. Building on our novel discovery that HDL (good cholesterol) lowers blood glucose, we will test whether HDL elevation over a month with a new drug (RVX-208) can improve glucose control in patients with pre-diabetes. If positive, these studies will support new therapeutic approaches to raise levels of circulating HDL for indications beyond vascular disease to manage type 2 diabetes.
Enhancing The Blood-brain Barrier Efflux Of ?-amyloid: A Novel Approach For The Treatment Of Alzheimer’s Disease
Funder
National Health and Medical Research Council
Funding Amount
$291,274.00
Summary
Alzheimer’s disease (AD) is the leading cause of dementia and is associated with the accumulation of a toxic protein in the brain. This project will investigate whether enhancing the removal of this toxic protein from the brain (by shuttling it into the blood) will restore the memory deficit associated with AD. The outcomes of this project have the potential to lead to novel strategies for the treatment of this debilitating disorder.