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
Mechanisms Regulating Excitation-contraction Coupling In Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$687,750.00
Summary
Muscle contraction occurs when an electrical impulse from a nerve travels over the surface of a skeletal muscle fibre and triggers the release of calcium ions from special stores inside the fibre. However, little is known about the regulatory mechanisms involved in turning on and turning off the calcium release. This project investigates the properties of the calcium release and what processes are involved in regulating it. Information about this is vital for understanding how normal muscle work ....Muscle contraction occurs when an electrical impulse from a nerve travels over the surface of a skeletal muscle fibre and triggers the release of calcium ions from special stores inside the fibre. However, little is known about the regulatory mechanisms involved in turning on and turning off the calcium release. This project investigates the properties of the calcium release and what processes are involved in regulating it. Information about this is vital for understanding how normal muscle works and why muscles show reduced performance with exercise (muscle fatigue), with aging, and in certain diseases.Read moreRead less
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
Regulation Of Nuclear Calcium Concentration In The Life Or Death Of Cells
Funder
National Health and Medical Research Council
Funding Amount
$195,047.00
Summary
The nucleus is the most prominent of all cell organelles and contains the primary genetic material for cellular development and growth. It performs some of the most important functions in the life and death of all living cells. However, little is known about many of the regulatory signals and events that control nuclear function. We will use new genetically-encoded sensor molecules that a living cell can be instructed to produce at various internal locations to explore important features of cell ....The nucleus is the most prominent of all cell organelles and contains the primary genetic material for cellular development and growth. It performs some of the most important functions in the life and death of all living cells. However, little is known about many of the regulatory signals and events that control nuclear function. We will use new genetically-encoded sensor molecules that a living cell can be instructed to produce at various internal locations to explore important features of cell control. This study will look specifically at how changes in the concentration of ionised Ca2+ in the nucleus control the switching on of genes and the initiation of programmed cell death pathways. This information is of significance to our understanding of normal cell growth and development, as well as abnormal growth (e.g. cancer).Read moreRead less
ER Stress-Unfolded Protein Response A Critical Metabolic Pathway For Airway Remodelling In Asthma
Funder
National Health and Medical Research Council
Funding Amount
$789,475.00
Summary
Airway remodelling in asthma is associated with poor clinical outcomes and is not prevented by current treatments. We have found endoplasmic reticulum stress (ERS) and associated unfolded protein response (UPR), a crucial process involve in cellular protein folding, play a key role in airway remodelling in asthma. This study will investigate whether inhibition of ERS prevents goblet cell metaplasia, mucus hypersecretion and fibrosis and can be used as a therapeutic strategy for severe asthma.
The Role Of Endoplasmic Reticulum (ER) Stress In Pancreatic Beta-cell Dysfunction.
Funder
National Health and Medical Research Council
Funding Amount
$85,775.00
Summary
Diabetes results from pancreatic ß-cell failure which is characterised by insulin secretory defects and ß-cell destruction. This is mediated by inflammatory cytokines in type 1 diabetes and by high levels of fat in type 2 diabetes. The mechanisms by which ß-cells fail remain to be clarified but they are important considering the current epidemic of diabetes in Australia. This project will enhance our understanding of ß-cell failure and may provide therapeutic targets for diabetes treatment.
Despite the high mortality associated with colon cancer only limited therapy options are available to treat these cancers. Here we propose a new strategy for inhibiting colon cancers driven by a specific type of mutations. Our preliminary data show that loss of DNA encoding a tumor suppressor gene creates a unique vulnerability in colon cancers. The aim of this proposal is to exploit this vulnerability as a strategy for combating colon cancer.
The proposal focuses on a novel angle explaining how pancreatic beta cells normally match their insulin synthesis, storage and secretion in response to an enhanced demand as occurs during obesity, and how this fails in the progression to Type 2 diabetes. In particular we will expand our discovery that glucose rapidly enhances the synthesis of a novel factor regulating gene transcription. This will generate basic knowledge that will potentially help design of novel therapies for Type 2 diabetes.