The Effect Of Ischaemia And Reperfusion On Sarcoplasmic Reticulum Calcium Handling In The Heart
Funder
National Health and Medical Research Council
Funding Amount
$236,208.00
Summary
Ischaemic heart disease is one of the most common causes of premature death in our society. Ischaemia occurs when the blood flow to the heart is obstructed so that oxygen cannot get to the muscle cells and metabolic waste products cannot be washed away. During ischaemia the concentration of free calcium within a cardiac muscle cell increases, and when blood flow is returned to the muscle this calcium concentration can increase further to very high levels. It is this change in calcium that is res ....Ischaemic heart disease is one of the most common causes of premature death in our society. Ischaemia occurs when the blood flow to the heart is obstructed so that oxygen cannot get to the muscle cells and metabolic waste products cannot be washed away. During ischaemia the concentration of free calcium within a cardiac muscle cell increases, and when blood flow is returned to the muscle this calcium concentration can increase further to very high levels. It is this change in calcium that is responsible for the reduced muscle force and abnormal cardiac rhythm that are the main cause of death. Cardiac muscle cells contain an intracellular compartment called the sarcoplasmic reticulum (SR). Under normal conditions the SR stores large amounts of calcium in order to maintain a low concentration of calcium free within the cell. However, even in a resting cell, calcium can escape from the SR through channels in SR membrane. We are using a state-of-the-art microscope to visualize these tiny packets of calcium, termed calcium sparks, as they travel through the SR membrane. If the number of calcium sparks increases, the amount of calcium being released from the SR also increases. We are studying what happens to calcium sparks, and therefore SR calcium release, during ischaemic heart disease. We are also examining the effect of ischaemic heart disease on the concentration of calcium within the SR and the activity of the transporters that pump calcium back into the SR. We hope to show that a change in the way the SR regulates calcium contributes to ischaemic damage. Understanding how changes in SR function alter muscle force and cardiac rhythm will help in the development of drugs to protect against ischaemic damage.Read moreRead less
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
STIM1 And Orai1 Proteins In Store-operated Calcium Entry In Liver
Funder
National Health and Medical Research Council
Funding Amount
$516,552.00
Summary
The liver plays a central role in controlling vital functions of the body. Changes in calcium level in the liver cells regulate most their functions, including fat and carbohydrate metabolism. There is ample evidence that suggests that diseases such as fatty liver and cholestasis affect the control of calcium in the liver. This research will investigate the mechanisms of calcium homeostasis in the liver and provide information for development of new approaches for treating liver disease.
Mimicking Protein Surfaces With Cyclic Peptides: W-conotoxin GVIA Mimics As Novel Analgesic And Neuroprotective Agents
Funder
National Health and Medical Research Council
Funding Amount
$216,412.00
Summary
The omega-conotoxins are small polypeptides (of around 25 residues) cross-linked by three disulfide bonds. At least two of these, omega-conotoxins GVIA and MVIIA, are potent and selective blockers of N-type voltage-gated calcium channels. Administered to the CNS via an intrathecal catheter, MVIIA and GVIA are analgesic in acute, chronic and neuropathic pain models, and protective following ischaemia-induced neuronal injury, such as occurs following stroke. They do not suffer from the development ....The omega-conotoxins are small polypeptides (of around 25 residues) cross-linked by three disulfide bonds. At least two of these, omega-conotoxins GVIA and MVIIA, are potent and selective blockers of N-type voltage-gated calcium channels. Administered to the CNS via an intrathecal catheter, MVIIA and GVIA are analgesic in acute, chronic and neuropathic pain models, and protective following ischaemia-induced neuronal injury, such as occurs following stroke. They do not suffer from the development of tolerance, in contrast with the opioids, such as morphine, which lose their analgesic potency over time and have undesirable side effects. We have determined the three-dimensional structure of GVIA and mapped onto that structure its calcium channel binding surface. This information is a starting point for the structure-based design of truncated and stabilised peptidic analogues of GVIA, which should have several advantages over the native polypeptides as candidates for the treatment of chronic pain and ischaemia-induced neuronal damage. In the course of this work we shall also generate a range of libraries of experimentally determined and predicted structures based on small, cyclic peptides. These libraries will be valuable tools for mimicking key functional regions of protein surfaces in small molecules that are easily (and cheaply) synthesised and have potentially favourable bioavailability. Thus, this project will also increase our understanding of the attributes of small cyclic peptides as mimics of functionally important protein surfaces and provide valuable tools for the design and evaluation of such peptides.Read moreRead less
Determining The Cellular Mechanisms Involved In The Airway Response To Topical Citrate
Funder
National Health and Medical Research Council
Funding Amount
$444,491.00
Summary
The air passages of the lungs are lined by mucous membranes. These membranes are covered by a thin layer of fluid to protect the airways from drying. This fluid allows the cilia, the hair like projections on top of the airway cells to beat more effectively to remove mucous and inhaled particles from the lungs. The volume and composition of this fluid is determined by the salt and water movement across the mucous membranes of the airways. These processes are abnormal in cystic fibrosis (CF), the ....The air passages of the lungs are lined by mucous membranes. These membranes are covered by a thin layer of fluid to protect the airways from drying. This fluid allows the cilia, the hair like projections on top of the airway cells to beat more effectively to remove mucous and inhaled particles from the lungs. The volume and composition of this fluid is determined by the salt and water movement across the mucous membranes of the airways. These processes are abnormal in cystic fibrosis (CF), the most common lethal inherited disease affecting Australians. In CF, an abnormal gene disrupts one of the major mechanisms for salt and water movement in the air passages. This abnormal salt transport causes drying of the airway surface which impairs the working of the cilia. This leads to retention of mucous in the airways with repeated bacterial infections damaging the lungs. Over the last 10 years, we have developed a series of simple tests to measure the abnormalities in the CF airway of human subjects. We have isolated an exciting new clinical application for sodium citrate, a substance used in blood transfusions. Citrate appears to alter both the salt transport abnormalities found in CF. This research proposal seeks to better understand the dual effects of citrate and to test similar compounds that may have stronger effects. The ultimate aim of our research is to have sufficient knowledge to work out the best way to develop a new treatment for CF.Read moreRead less