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
Receptor Signalling Through Intracellular Calcium Stores In Chromaffin Cells
Funder
National Health and Medical Research Council
Funding Amount
$461,000.00
Summary
The function of cells in the body is controlled by many hormones and neurotransmitters acting on the cell's surface. Hormones and transmitters mediate their effects by producing chemical signals within the cell that regulate its activities. One key cell signalling chemical is calcium, especially in nerve cells which have developed sophisticated mechanisms for using calcium to control their function. Recently, new levels of complexity have been discovered, both in how cell calcium levels are modi ....The function of cells in the body is controlled by many hormones and neurotransmitters acting on the cell's surface. Hormones and transmitters mediate their effects by producing chemical signals within the cell that regulate its activities. One key cell signalling chemical is calcium, especially in nerve cells which have developed sophisticated mechanisms for using calcium to control their function. Recently, new levels of complexity have been discovered, both in how cell calcium levels are modified by hormones and transmitters and in how these complex calcium signals are used by cells to control their function. This project will investigate how hormones and transmitters can produce different types of calcium signals in nerve cells, and how these signals affect different aspects of the nerve cell's function. In particular, it will establish how two different types of specialised calcium stores within nerve cells are used by different classes of hormone and transmitter, and the distinct cellular functions these two calcium stores can regulate. The results will provide fundamental new information on how nerve cells control their activity and may help identify potential new targets for drugs.Read moreRead less
Intracellular Calcium Signalling And Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$295,357.00
Summary
The liver is responsible for regulating the metabolism of carbohydrates and fats, the synthesis of proteins which transport fats around the body, the synthesis of bile required for fat digestion, and for the removal of toxic chemicals from the body. Many of these processes are controlled by hormones such as adrenaline and insulin. The actions of these and other hormones on the liver involves changes in the concentration of calcium in liver cells. In a number of diseases such as diabetes, fat mal ....The liver is responsible for regulating the metabolism of carbohydrates and fats, the synthesis of proteins which transport fats around the body, the synthesis of bile required for fat digestion, and for the removal of toxic chemicals from the body. Many of these processes are controlled by hormones such as adrenaline and insulin. The actions of these and other hormones on the liver involves changes in the concentration of calcium in liver cells. In a number of diseases such as diabetes, fat malabsorption, and liver failure, the balance and regulation of calcium in liver cells is abnormal. The aims of the present experiments are to investigate the mechanisms by which hormones regulate the flow of calcium into liver cells. The experiments will involve the measurement of calcium in different regions of liver cells using fluorescent dyes and high resolution microscopy, and the identification of structural proteins and organelles within the liver cell which are required to control calcium inflow. The results should show how an important type of calcium channel in liver cells works and is controlled. This knowledge will allow better treatment of diabetes, fat malabsorption and liver failure. The knowledge should also lead to improvements in liver transplant operations.Read moreRead less
Targeting TRPV4 Activation Mechanisms To Reveal Novel Pain Therapies
Funder
National Health and Medical Research Council
Funding Amount
$580,938.00
Summary
Pain nerves sense painful chemical and physical stimuli, by opening protein "ion channels" which let small electric currents traverse the cell membrane. This pain signal is transmitted to the spinal cord and then the brain, where it is perceived as pain and elicits a reaction. But we don't know how the ion channels open. This project will investigate how receptors for painful substances open ion channels to cause pain. Understanding this mechanism will help us to make new drugs to treat pain.
Store-operated Calcium Channels And Liver Function
Funder
National Health and Medical Research Council
Funding Amount
$241,477.00
Summary
The liver is responsible for regulating the metabolism of carbohydrates and lipids , the synthesis of proteins responsible for the transport of lipids in the blood, the synthesis of bile required for fat digestion, and for the removal of toxic chemicals from the body. Many of these processes are regulated by the changes in the free calcium concentration in the cytoplasmic space of liver cells. In a number of diseases such as diabetes, fat malabsorption, and liver failure, the balance and regulat ....The liver is responsible for regulating the metabolism of carbohydrates and lipids , the synthesis of proteins responsible for the transport of lipids in the blood, the synthesis of bile required for fat digestion, and for the removal of toxic chemicals from the body. Many of these processes are regulated by the changes in the free calcium concentration in the cytoplasmic space of liver cells. In a number of diseases such as diabetes, fat malabsorption, and liver failure, the balance and regulation of calcium concentrations in liver cells is abnormal. The cytoplasmic calcium signal can come either from the extracellular space, through channels in plasma membrane, or from the intracellular calcium-storing organelles. The aims of the present proposal are to investigate the properties of the calcium channels in the liver cell plasma membrane, and the mechanisms by which they are regulated. The experiments will involve the direct estimation of calcium inflow into liver cells, measured as an electric current through the plasma membrane by patch-clamp technique. The results should show how calcium channels in liver cells work and provide knowledge that can be used for better treatment of diabetes, fat malabsorption and liver failure.Read moreRead less
The Role Of Na-Ca Exchange Current In Cardiac Pacemaker Cells
Funder
National Health and Medical Research Council
Funding Amount
$263,100.00
Summary
The heart rate is controlled by a small group of pacemaker cells within the heart. The pacemaker cells fire spontaneously and this intrinsic rate is modified by the sympathetic and parasympathetic nerves of the autonomic nervous system. We are studying a new current in the pacemaker cells which helps to control the firing rate. This new current is controlled by the intracellular calcium inside the cells so we are also studying the way in which intracellular calcium changes when the autonomic ner ....The heart rate is controlled by a small group of pacemaker cells within the heart. The pacemaker cells fire spontaneously and this intrinsic rate is modified by the sympathetic and parasympathetic nerves of the autonomic nervous system. We are studying a new current in the pacemaker cells which helps to control the firing rate. This new current is controlled by the intracellular calcium inside the cells so we are also studying the way in which intracellular calcium changes when the autonomic nervous system is active. This project will provide new insights into the function of this small group of critical cells and may allow treatment of some cardiac arrhythmias without the expense and surgery involved in the use of artificial pacemakers.Read moreRead less
Aberrant Behaviour Of Cardiac Calcium Release Channels Induced By Ryanodine Receptor Peptide Probes
Funder
National Health and Medical Research Council
Funding Amount
$315,375.00
Summary
Contraction of heart muscle is regulated by the release of calcium ions from an intracellular store known as the sarcoplasmic reticulum. Calcium is released from this store to trigger contraction and then taken up again to let the heart muscle relax. Calcium flows out from the store through a specialised type of ion channel protein known as the ryanodine receptor. Recently, genetic studies have indicted that some forms of sudden cardiac death are due to mutations in the ryanodine receptor in the ....Contraction of heart muscle is regulated by the release of calcium ions from an intracellular store known as the sarcoplasmic reticulum. Calcium is released from this store to trigger contraction and then taken up again to let the heart muscle relax. Calcium flows out from the store through a specialised type of ion channel protein known as the ryanodine receptor. Recently, genetic studies have indicted that some forms of sudden cardiac death are due to mutations in the ryanodine receptor in the heart of susceptible individuals. However, nothing is currently known about how such mutations affect the function of the ryanodine receptor or how this can cause the abnormal heart beating that leads to sudden cardiac death. This project will investigate the normal functioning of the ryanodine receptor and what aberrations occur with the different mutations. This could lead to better treatment of individuals susceptible to this type of sudden cardiac death. The effectiveness of one type of drug in preventing aberrant channel behaviour will also be examined.Read moreRead less
Excitation-contraction Coupling In Skeletal Muscle In Health, Exercise And Disease
Funder
National Health and Medical Research Council
Funding Amount
$623,621.00
Summary
Skeletal muscle dysfunction occurs in certain diseases, aging and exercise, and can deleteriously affect lifestyle and mobility. This project investigates the molecular mechanisms involved in the complex sequence of events that occur in each individual muscle fibre, starting from stimulation by a nerve through to the fibre contracting. This should give information about causes of skeletal muscle dysfunction in myotonia, heart failure and other situations, and help development of therapies.