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.
Motor Neurone Disease - Pathophysiological Insights Into The Site Of Origin And Patterns Of Neurodegeneration.
Funder
National Health and Medical Research Council
Funding Amount
$309,361.00
Summary
Motor neurone disease (MND) kills one Australian per day and is characterised by progressive loss of the corticospinal tract, that controls all voluntary movements. The present project will investigate where MND begins and document how the loss of nerves within the brain, spinal cord and peripheral nerves evolves. In addition to providing information about prognosis, new quantifiable measures will be developed to objectively monitor patients in future treatment and prevention trials.
The Role Of Oxidative Stress In The Patho-aetiology Of Prion Disorders Using Infected Cell Culture And Animal Models
Funder
National Health and Medical Research Council
Funding Amount
$112,014.00
Summary
The transmissible spongiform encephalopathies (TSE; also known as prion diseases) are a biologically unique and fascinating group of invariably fatal diseases which primarily affect the brains of both humans and animals. In humans, sporadic Creutzfeldt-Jakob disease (CJD) is the most common form, while in animals it is the recent epidemic of bovine spongiform encephalopathy (mad cow disease), and its probable transmission to humans as new variant CJD, which has drawn so much attention to this gr ....The transmissible spongiform encephalopathies (TSE; also known as prion diseases) are a biologically unique and fascinating group of invariably fatal diseases which primarily affect the brains of both humans and animals. In humans, sporadic Creutzfeldt-Jakob disease (CJD) is the most common form, while in animals it is the recent epidemic of bovine spongiform encephalopathy (mad cow disease), and its probable transmission to humans as new variant CJD, which has drawn so much attention to this group of disorders. The preponderance of scientific evidence now supports the belief that infectivity in TSEs relates predominantly (probably exclusively) to a protein (called the prion protein; PrP) which is normally found on the cell surface of a number of types of brain cells, including neurons. Transmissibility, and hence infectivity, is more correctly associated with a malfolded version of PrP into an abnormal shape which gives the mutant protein significantly different biological and biochemical properties, including relative resistance to breakdown by enzymes that metabolise proteins (proteases) and enhanced tendency to aggregate. However, the precise steps involved in this transformation to the abnormal infectious form of PrP are not known. Similarly, our understanding of how different folding and accumulation of this protein brings about disease is not clear. Nevertheless, as with other neurological diseases (eg Alzheimer's disease) which are a consequence of unexplained spontaneous premature degeneration of parts of the brain (neurodegenerative diseases), oxidative stress is increasingly believed to play a role. Oxidative stress is a generic term used to describe the enhanced production within a cell of small, very harmful, oxygen containing molecules which under normal circumstances can be successfully detoxified. This project involves a detailed study of the role of oxidative stress in the causation of prion diseases using both mouse and cell culture models.Read moreRead less
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