Cortical Spreading Depressions: Effects On Intracellular Ca2+ Concentration And Mechanisms Of Propagation
Funder
National Health and Medical Research Council
Funding Amount
$185,604.00
Summary
Human neuropathologies such as migraine, stroke, focal epilepsy and head injury all appear to involve an event called cortical spreading depression (CSD). This is characterised by a transient loss of excitability of cells that slowly spreads from a site of initiation out across the cortical surface. In normal brain tissue CSDs do not kill cells but in tissue with less than optimal energy supply CSDs do kill cells. This project is designed to understand the mechanisms contributing to CSD-induced ....Human neuropathologies such as migraine, stroke, focal epilepsy and head injury all appear to involve an event called cortical spreading depression (CSD). This is characterised by a transient loss of excitability of cells that slowly spreads from a site of initiation out across the cortical surface. In normal brain tissue CSDs do not kill cells but in tissue with less than optimal energy supply CSDs do kill cells. This project is designed to understand the mechanisms contributing to CSD-induced cell death. It is widely accepted that a high intracellular concentration of calcium ions is lethal to a cell. Thus, the proposed experiments are expected to show that a single episode of CSD in normal brain tissue induces only small changes in the intracellular calcium ion concentration but if repeated episodes of CSD occur, and if they take place in tissue with a compromised energy supply, then the calcium concentration rises to detrimental levels. Little is known about the mechanisms which underlie the propagation of CSD and therefore experiments will also be undertaken to investigate whether release of a messenger into the extracellular space is important or if there is a role for release of calcium from intracellular stores.Read moreRead less
Role Of Calcium Stores And Phosphate Channels In Muscle Fatigue
Funder
National Health and Medical Research Council
Funding Amount
$221,640.00
Summary
Muscles become weaker when ever they are used intensively; this is the familiar muscle fatigue. We are studying the mechanism of muscle fatigue and believe it is caused by depletion of a store of calcium inside the muscle. We suspect the store of calcium declines because phosphate, which is a product of muscle metabolism, enters the calcium store and precipitates as calcium phosphate. Currently we are trying to prove this hypothesis and extend it by studying the channels through which phosphate ....Muscles become weaker when ever they are used intensively; this is the familiar muscle fatigue. We are studying the mechanism of muscle fatigue and believe it is caused by depletion of a store of calcium inside the muscle. We suspect the store of calcium declines because phosphate, which is a product of muscle metabolism, enters the calcium store and precipitates as calcium phosphate. Currently we are trying to prove this hypothesis and extend it by studying the channels through which phosphate passes from the muscle cell into the calcium store. It may be possible to find or design drugs which minimise the movement of phosphate through this channel and such a drug might reduce the component of fatigue caused by this mechanism. Such a drug might benefit patients whose normal activities are limited by muscle fatigue; this includes patients with any disabling muscle disease, such as muscular dystrophy or stroke, and patients with heart failure. In addition elderly people suffer a loss of muscle bulk and the remaining muscle is easily fatigued causing loss of mobility and independence; so the elderly might also benefit from such a drug.Read moreRead less
Unique Isoform-specific Regulation Of Cardiac Ryanodine Receptors By Calcium Store Proteins
Funder
National Health and Medical Research Council
Funding Amount
$421,160.00
Summary
The importance of proteins that regulate calcium stores of heart muscle is graphically illustrated by massive changes in cell structure and function, which lead to ventricular fibrillation and fatality when the proteins are disrupted. We recently made the remarkable discovery that the proteins have a unique action in the heart which enhances cardiac contraction. We will discover the interaction sites between the proteins and will define novel therapeutic targets for heart failure.
Assessment Of Calcium Signaling In Breast Cancer Cells Associated With Epithelial-mesenchymal Transition
Funder
National Health and Medical Research Council
Funding Amount
$116,762.00
Summary
This research will assess the role of specific proteins that control cell function in a process which is important in the spread of cancer cells throughout the body. The work is aimed at identifying new targets for drugs that may be used to prevent or stop the spread of breast cancer cells to other organs such as the brain and liver.
Calcium acts as a signal to control cell processes important in cancer. The entry of calcium into the cell is regulated by calcium channels and we have found some channels are over-expressed in breast cancer. Altering the expression and activity of these calcium channels is a possible therapeutic approach for cancer. We will determine the reasons and consequences of alterations of calcium channels in breast cancer and whether they are viable anti-cancer therapies and biomarkers.
Anthracyclines Disrupt Ca2+ Signalling In Cardiomyocytes: A Contribution To Cardiac Toxicity
Funder
National Health and Medical Research Council
Funding Amount
$525,620.00
Summary
Anthracyclines are one of the most effective drugs used in chemotherapy, but cause side effects resulting in serious heart problems which can be fatal. The link between anthracycline therapy and the problems they cause in the heart is not fully defined. We will investigate mechanisms leading to these side effects and define specific targets of anthracyclines in the heart. It is hoped this will lead to the design of new drugs which counteract the side effects of anthracycline treatment.
Calcium Signaling And Epithelial-mesenchymal Transition: A New Approach To Identifying Pharmacological Targets For Metastasis
Funder
National Health and Medical Research Council
Funding Amount
$561,645.00
Summary
The largest killer of women with breast cancer is disease that has spread e.g. to brain, bones, lungs. Once breast cancer has spread in this way to secondary sites, also known as metastatic disease, then there is limited treatment available and generally therapy is palliative only. Our work describes experiments that will help us understand the process of metastasis and provide new avenues for drug discovery in metastatic disease, thus helping women who have a poor prognosis.