Antibody-directed Delivery Of Anti-restenotic Agents Using Inorganic Nanoparticles
Funder
National Health and Medical Research Council
Funding Amount
$327,151.00
Summary
Arteries that have been surgically treated to remove fatty lesions that block blood flow frequently become re-blocked (restenosed), and drugs to prevent this re-blockage often have bad side-effects. We propose to prevent these complications by target-delivering the drugs directly and only to the required site using a single injection at the time of surgery. This will limit systemic side-effects, treatment costs and incidence of reblocking and bleeding complications.
Novel Small Molecule FosB/AP-1 Inhibitors For The Prevention Of Proliferative Vascular Disorders
Funder
National Health and Medical Research Council
Funding Amount
$343,597.00
Summary
This project examines the effect of a novel FosB/AP-1 inhibitor (LK001) on neointima formation after injury in animal models of restenosis, atherosclerosis and abdominal aortic aneurysm, and a human ex vivo model of graft stenosis Given the current prevalence of CVD in Australia and the increasing demographic of susceptible individuals in the ageing population, this project has enormous clinical implications.
Lipoprotein Oxidation, Antioxidants And Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$281,812.00
Summary
We are studying how major blood vessels harden. This process (called atherosclerosis) is the major underlying cause of heart disease, the major single cause of death of Australians. Our research focusses on the 'Oxidation Theory', one of the most common theories of how atherosclerosis develops. Accordingly, fats in fat-carrying particles (called lipoproteins) penetrate the walls of blood vessels, where they cause disease as a result of going rancid. This is a primary reason for the general publi ....We are studying how major blood vessels harden. This process (called atherosclerosis) is the major underlying cause of heart disease, the major single cause of death of Australians. Our research focusses on the 'Oxidation Theory', one of the most common theories of how atherosclerosis develops. Accordingly, fats in fat-carrying particles (called lipoproteins) penetrate the walls of blood vessels, where they cause disease as a result of going rancid. This is a primary reason for the general public's interest in antioxidant supplements to combat heart disease. However, it is not clear at present whether rancid fats is a cause or consequence of atherosclerosis, and we recently showed that the two processes can be dissociated in an animal model of the disease. This application addresses the question of whether the process of fats going rancid can be generally dissociated from atherosclerosis, using several different animal models of the disease. We will distinguish different chemical pathways that give rise to different types of rancid fats, and between rancid fats and 'rancid' proteins. Such studies have not been carried out to date. Our underlying hypothesis is that the process of lipoprotein fat going rancid is a consequnece rather than a cause of atherosclerosis and heart disease. By testing this hypothesis, we will provide a rationale for whether antioxidant supplements aimed at preventing rancid fats from accumulating are likely of benefit in terms of preventing heart disease. This is of direct interest to public health. Our studies also address the issue of how antioxidants (if not through preventing fats from going rancid) attenuate atherosclerosis. We will focus on a particular synthetic antioxidant for which there is strong evidence that it is beneficial in preventing the re-narrowing of blood vessels in humans undergoing coronary angioplasty. These studies have the potential to provide new clues for the development of novel drugs against heart disease.Read moreRead less
Cleavage Methods Of Mutation Detection: Improvement And Application In Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,044,349.00
Summary
Genes contain the information to build our body and keep it operating normally. These genes are inherited from our parents and number around 100,000. Faults in these genes can cause inherited diseases such as cystic fibrosis, cancers and common disorders such as Asthma and diabetes. These genes need detecting so that particular genes can be identified as causing the disease and also so that patients can have their disease properly diagnosed so that proper therapy and information can be given to ....Genes contain the information to build our body and keep it operating normally. These genes are inherited from our parents and number around 100,000. Faults in these genes can cause inherited diseases such as cystic fibrosis, cancers and common disorders such as Asthma and diabetes. These genes need detecting so that particular genes can be identified as causing the disease and also so that patients can have their disease properly diagnosed so that proper therapy and information can be given to the patients. In future similar changes (but changes not causing disease) may be searched for in patients to overcome the side effects of drugs. Our centre specializes in the methods of detecting faults and their application. Two of our methods are being used around the world and one is being sold as simple kit. These methods still have drawbacks and the work proposed is to overcome some of these. We propose to apply our and other methods to faults in genes which have recently been shown to cause diseases of the artery. This is an exciting new development that shows that this disease is similar to cancer. We are fortunate to have attracted Dr Paula Bray from the laboratory which discovered this. This new finding needs to be studied in more detail and may identify life-style factors which cause coronary heart disease. Our studies will also assist in gene therapy when it becomes available.Read moreRead less
Targetting The NADPHoxidase Source Of Reactive Oxygen Species In Vascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$552,250.00
Summary
In Australia, coronary heart disease (CHD) leading to heart attacks or strokes is 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, appears to be an important cause of CHD, heart attacks and strokes. We seek to understand how such oxyradicals are produced in the cells that make up the artery wall. Using novel DNA-type molecules we have recently discovered that a protein called Nox4 is ....In Australia, coronary heart disease (CHD) leading to heart attacks or strokes is 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, appears to be an important cause of CHD, heart attacks and strokes. We seek to understand how such oxyradicals are produced in the cells that make up the artery wall. Using novel DNA-type molecules we have recently discovered that a protein called Nox4 is crucial for the production of oxygen free radicals by blood vessels. Furthermore, we have identified a class of drugs that selectively block the activity of Nox4 in blood vessels. We now wish to directly test whether inhibiting Nox4, either with DNA-type molecules, various drugs known to block Nox4, or by complete elimination of the Nox4 gene in mice, prevents the development of CHD in animal models. This work will not only advance our understanding of the origin of vascular oxidative damage but will also allow us to identify novel therapeutic targets in the treatment of cardiovascular diseases that are associated with increased oxidative stress. The same drugs and molecules might also prove useful for improving recovery from heart attacks and strokes, for Nox4 may be turned on in the heart and brain in these conditions. Information obtained in our study will be useful in directing future prescription practices in clinical management of CHD and stroke, and for designing new therapeutic compounds for CHD.Read moreRead less
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