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Identification Of Cardiac Sarcoplasmic Reticulum Targets For Cardiotoxic Drugs
Funder
National Health and Medical Research Council
Funding Amount
$265,986.00
Summary
Anthracyclines are drugs which are used successfully in chemotherapy. Unfortunately, these drugs can lead to serious heart problems which sometimes result in death, and the mechanisms behind this remain elusive. Finding the specific targets of these drugs and how these drugs affect heart contraction may lead to designing drug cocktails which protect the heart from side effects.
How Does Oxygen Regulate Ca2+ Channel Function In Cardiac Myocytes?
Funder
National Health and Medical Research Council
Funding Amount
$475,517.00
Summary
Oxygen occupies a key role in cellular metabolism and function. Oxygen delivery to cells is critical and lack of oxygen such as occurs during a heart attack can be lethal. Death occurs commonly by induction of arrhythmia or a disturbance in the heart beat. The abnormal heart beat cannot enable the heart to pump blood efficiently and vital organs are then deprived.Exactly how arrhythmia is induced is not understood. The normal heart beat occurs as a result of propogation of electrical signals thr ....Oxygen occupies a key role in cellular metabolism and function. Oxygen delivery to cells is critical and lack of oxygen such as occurs during a heart attack can be lethal. Death occurs commonly by induction of arrhythmia or a disturbance in the heart beat. The abnormal heart beat cannot enable the heart to pump blood efficiently and vital organs are then deprived.Exactly how arrhythmia is induced is not understood. The normal heart beat occurs as a result of propogation of electrical signals through heart muscle cells. The electrical activity is generated and sustained by movement of salts or ions through membrane proteins known as ion channels. One of these channels, the L-type calcium channel plays a vital role in cardiac excitation and contraction. A reduction in oxygen alters the function of the L-type calcium channel. However, the exact mechanism for this is uncertain. An oxygen sensing mechanism in the cell is responsible for the regulation of channel function during hypoxia. The exact identity of the oxygen sensor is currently the centre of debate. Four hypotheses have been proposed. This proposal aims to examine in detail the four hypotheses of oxygen sensing to definitively determine the identity of the oxygen sensor. This information should increase our understanding of how calcium channels function during stressful conditions such as during a heart attack.Read moreRead less
The Role Of Glutathionylation In Redox Modification Of L-type Ca2+ Channel Function During Oxidative Stress In The Heart
Funder
National Health and Medical Research Council
Funding Amount
$402,898.00
Summary
The L-type calcium channel is a protein in the membrane of heart muscle cells responsible for regulating the entry of calcium into cells and maintaining normal heart rhythm and contraction. We have shown that reactive oxygen species can regulate the function of the calcium channel. We are now interested in determining whether a direct modification of the channel protein known as glutathionylation is responsible for altered channel function during oxidative stress such as after a heart attack.
The Role Of Calcium And TRPC Channels In Sinoatrial Node Ageing
Funder
National Health and Medical Research Council
Funding Amount
$385,301.00
Summary
The failure of pacemaker function is a common clinical problem in the elderly who become more susceptible to cardiac arrhythmias. We recently discovered a new calcium channel called the transient receptor potential canonical channel (TRPC) in the pacemaker cells. The aim of this research is to study the role of TRPC channels in pacemaker ageing. Improved understanding of the mechanisms of the pacemaker ageing may provide new therapeutic strategies for reducing the risk of cardiac arrhythmias.
Primary Cardiac Hypertrophy - A Functional Genetic Approach To Investigate Cellular Mechanisms Of Metabolic Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$226,692.00
Summary
Population studies have recently shown that enlargement of the heart, even when blood pressure is normal, is a risk factor which can lead to cardiovascular complications. Very little is known about the alterations in heart cell structure and function which occur in cardiac enlargement not complicated by high blood pressure. It is possible that specific metabolic abnormalities underlie this condition. The goal of this study is to use a newly developed genetically manipulated experimental animal m ....Population studies have recently shown that enlargement of the heart, even when blood pressure is normal, is a risk factor which can lead to cardiovascular complications. Very little is known about the alterations in heart cell structure and function which occur in cardiac enlargement not complicated by high blood pressure. It is possible that specific metabolic abnormalities underlie this condition. The goal of this study is to use a newly developed genetically manipulated experimental animal model to study the function of single heart cells. In this model one of the glucose transporters has been deleted. Our goal is to compare heart function in this genetic model with heart function in diabetes. Cells are isolated from hearts using enzyme treatments and investigated microscopically to determine if there are subcellular structural alterations. Functional studies are performed on individual viable cells using a combination of electrical recording techniques and fluorescence imaging methods. The experimental aim is to assess whether there is disruption of sodium, calcium or pH regulation associated with cardiac enlargement associated with metabolic abnormalities. This research will assist in identifying appropriate therapeutic strategies for intervention in the treatment or prevention of conditions associated with cardiac enlargement.Read moreRead less
Central Control Of Blood Pressure: Neurotransmitters, Receptors, Signal Transduction And Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$941,350.00
Summary
The way that the brain controls blood pressure is of crucial significance to our day-to-day survival. Nerves in the lower brain and spinal cord cause blood pressure to be maintained at appropriate levels for all types of daily activities ranging from sleep, when blood pressure is very low, to exercise when blood pressure can be very high. In hypertension, a disorder that afflicts around 10% of the community, blood pressure is elevated to an extent that damages organs such as the brain, heart, ki ....The way that the brain controls blood pressure is of crucial significance to our day-to-day survival. Nerves in the lower brain and spinal cord cause blood pressure to be maintained at appropriate levels for all types of daily activities ranging from sleep, when blood pressure is very low, to exercise when blood pressure can be very high. In hypertension, a disorder that afflicts around 10% of the community, blood pressure is elevated to an extent that damages organs such as the brain, heart, kidney and eye. It now appears that most cases of hypertension have as their basis a disorder of the way that the brain, through the sympathetic nervous system, controls the heart and blood vessels. Many different brain systems need to change the way that blood is distributed in the body at different times. For example, when we eat, blood goes preferentially to our gut; if we exercise, to our heart and muscles; if we are cold, to our skin and when we think, to our brain. This specialised regulation of blood flow is accomplished by the interaction of nerves in the lower brain and spinal cord. It involves a vast array of special chemical messengers acting on specific receptors through different intracellular mechanisms and involving the turning on or off of genes. Only a few of these neurotransmitter systems are well understood. At the core of our proposal, we aim to determine which neurotransmitters systems are important for which cardiovascular functions. We anticipate that this new information will permit the development of new approaches to the management of hypertension. The reason for this is that since different pathways use different messenger systems, it should become possible to tailor therapy to suit hypertension without causing undesirable side-effects.Read moreRead less
Thioredoxin Interacting Protein: A Novel Regulator Of Angiogenesis And Impaired Neovascularisation In Diabetes Mellitus
Funder
National Health and Medical Research Council
Funding Amount
$292,639.00
Summary
Heart disease is the leading cause of death and treatment options such as bypass surgery are unsuitable for many sufferers, particularly those with diabetes. This project investigates the regulation of new blood vessel growth through the action of antioxidants and also examines the contribution of adult stem cells to this process. Regulating new blood vessel growth provides a novel means to overcome current problems in the management of both non-diabetic and diabetic patients with heart disease.
Cardiovascular Reactivity To Stress: Role Of Redox Signalling In The Hypothalamus And Brainstem
Funder
National Health and Medical Research Council
Funding Amount
$606,979.00
Summary
Cardiovascular disease is Australia's greatest health problem. It kills more people than any other disease and affected 3.5 million Australians in 2004-05. More and more evidence suggests a relationship between the risk of cardiovascular disease and mental stress. But more research is needed on how stress contributes to heart disease risk. This project aims to determine the role of harmful molecules, called free oxygen radicals, in brain in mediating effects of stress on cardiovascular system.