Investigating The Involvement Of Human Derived Astrocytes And Motor Neurons In The Pathology Of Motor Neuron Disease.
Funder
National Health and Medical Research Council
Funding Amount
$287,321.00
Summary
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease, which results in the death of nerves that innervate muscle, known as motor neurons. Recent studies using mouse ALS models showed that certain cells that normally support motor neurons may be directly contributing to their death in ALS. We propose to derive ALS-diseased human cells and investigate how these cells may react in ‘normal’ tissue. These studies are clinically relevant in understanding ALS pathological processes.
Aberrant Oligosaccharide Processing Of Nox2-oxidase As A Mechanism Of Vascular Oxidative Stress In Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$552,565.00
Summary
Excessive production of free radicals by an enzyme called Nox2 may be a cause of artery disease leading to heart attacks and strokes. This study will identify whether the addition of sugarchains to Nox2 causes it to be expressed at the surface of cells allowing the free radicals it produces to exit the cell and cause damage to the blood vessel wall. Charaterising this new pathway of excessive free radical production may pave the way for new diagnostics and treatments for artery disease.
Is NADPH Oxidase The Trigger For Accelerated Atherosclerosis Caused By Bacteria?
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
Cardiovascular disease is the leading cause of death and morbidity world-wide. However, its incidence is not fully explained by the presence of conventional risk factors, such as high cholesterol, hypertension, diabetes and cigarette smoking. Steadily growing evidence indicates that bacterial infection, particularly by Chlamydia pneumoniae and Helicobacter pylori, is also strongly linked to atherosclerotic lesion formation and increased risk of a cardiovascular event. This project will investiga ....Cardiovascular disease is the leading cause of death and morbidity world-wide. However, its incidence is not fully explained by the presence of conventional risk factors, such as high cholesterol, hypertension, diabetes and cigarette smoking. Steadily growing evidence indicates that bacterial infection, particularly by Chlamydia pneumoniae and Helicobacter pylori, is also strongly linked to atherosclerotic lesion formation and increased risk of a cardiovascular event. This project will investigate a new aspect to the body s defence against bacterial infection which involves production of oxygen radicals by the blood vessel wall. We propose that although this response of the artery to bacteria in the blood is beneficial in the short term, it inadverently initiates a chronic inflammatory process that ultimately accelerates development of artery disease. If this is the case, the oxygen radical production by the enzyme, NADPH oxidase, in the artery wall may represent the missing link between bacterial infection and atherosclerosis. We will therefore firstly test whether two bacteria, Chlamydia pneumoniae and Helicobacter pylori, can acutely induce artery inflammation in this way. We will then perform definitive studies to test whether mice infected with these bacteria develop accelerated atherosclerosis, and if so, whether this effect is dependent on NADPH oxidase activity in the artery wall. Finally, we will test the efficacy and importance of timing of antibiotic therapy to prevent atherosclerotic lesion formation.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
Regulation Of Vascular Tone By Indoleamine 2,3-dioxygenase
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
As part of their normal function, blood vessels dilate and contract, for example in response to the pulsative force with which our heart pumps the blood around the circulation. Blood vessels produce several different chemicals that cause vessel relaxation, and these vary depending on several factors, such as the blood vessel involved, its diameter and precise location within our body. In addition to responding to the pulsative nature of blood flow, blood vessels also respond to many other condit ....As part of their normal function, blood vessels dilate and contract, for example in response to the pulsative force with which our heart pumps the blood around the circulation. Blood vessels produce several different chemicals that cause vessel relaxation, and these vary depending on several factors, such as the blood vessel involved, its diameter and precise location within our body. In addition to responding to the pulsative nature of blood flow, blood vessels also respond to many other conditions, including certain diseases, so that it is not surprising that many of the commonly used cardiovascular drugs target to change blood vessel tone, either increasing or decreasing blood pressure, depending on the circumstances involved. The present application is based on the discovery, in the mouse, that during a systemic infection a specific protein is induced in the cells that line blood vessels. This protein degrades a certain amino acid into a novel chemical, called kynurenine. We observed that kynurenine has previously unrecognised vessel-relaxing properties. The present project will investigate the importance of kynurenine formation as a novel pathway in the regulation of vascular tone. Mice, in which the activity of the kynurenine-producing protein will be modulated (both up and down) will be used in conjunction with blood pressure and other relevant measurements. In addition, the role of a unique molecule, called superoxide anion radical, in the production of kynurenine by the protein will also be tested. If our results confirm that the protein and kynurenine are indeed involved in regulating vascular tone, our research could have tremendous impact on many aspects of normal physiology as well as cardiovascular diseases that remain the major single cause of death in Australia.Read moreRead less
Superoxide And The Nitric Oxide-peroxynitrite Pathway In Renal Ischaemia-reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$202,755.00
Summary
Acute renal failure is common and has 50% mortality. Free radicals are vey reactive, unstable molecules that alter normal metabolic reactions. The study aims to determine the role of oxygen-derived free radicals and nitric oxide and their interaction in renal ischaemic injury. The balance between the positive effects of nitric oxide on blood flow and the damaging effects of by-products of the reaction of nitric oxide with superoxide radical (peroxynitrite) on renal tubules may determine the exte ....Acute renal failure is common and has 50% mortality. Free radicals are vey reactive, unstable molecules that alter normal metabolic reactions. The study aims to determine the role of oxygen-derived free radicals and nitric oxide and their interaction in renal ischaemic injury. The balance between the positive effects of nitric oxide on blood flow and the damaging effects of by-products of the reaction of nitric oxide with superoxide radical (peroxynitrite) on renal tubules may determine the extent of cell damage and hence recovery from ischaemic and hypoxic renal injury. Modulation of these opposing forces may lead to strategies to protect and improve renal function in acute renal failure in man.Read moreRead less