Glutathione Transferase-derived Compounds As Therapeutic Agents
Funder
National Health and Medical Research Council
Funding Amount
$418,516.00
Summary
Inhibition of cardiac calcium ion channels may be an effective new way of improving heart performance in patients with heart failure. This project will investigate how a glutathione transferase enzyme inhibits calcium ion channels in the heart and if small fragments of a muscle specific glutathione transferase can be used to specifically modify cardiac ryanodine receptor function. These fragments will provide the basis for the development of a new therapeutic approach.
Characteristics Of Splice Variants Of The Skeletal Muscle Ryanodine Receptor: Implications For Myotonic Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$258,000.00
Summary
The project is to address some of the basic molecular changes that occur in skeletal muscle during development and in myotonic dystrophy. Myotonic dystrophy is a significant health issue since it is the most common adult muscular dystrophy, with an occurrence of ~1 in 7000. The results will provide much needed information about the membrane-associated molecular mechanisms that regulate muscle contraction and may provide a basis for drug design and treatment of myotonic dystrophy. Respiration and ....The project is to address some of the basic molecular changes that occur in skeletal muscle during development and in myotonic dystrophy. Myotonic dystrophy is a significant health issue since it is the most common adult muscular dystrophy, with an occurrence of ~1 in 7000. The results will provide much needed information about the membrane-associated molecular mechanisms that regulate muscle contraction and may provide a basis for drug design and treatment of myotonic dystrophy. Respiration and locomotion depend on the release of calcium ions from stores inside muscle cells. Ryanodine receptor calcium channels regulate calcium release from the stores. The essential nature of ryanodine receptors is underlined by death at or before birth when ryanodine receptor expression is defective. In addition genetic defects in the ryanodine receptor cause cardiac arrhythmias, malignant hyperthermia and central core disease. Ryanodine receptor function is compromised in heart failure and fatigue. The essential role of ryanodine receptors makes them a potential therapeutic target, but they are not used in this way because of our limited knowledge of the protein. Myotonic dystrophy is an autosomal dominant multi-system disorder, in which an expansion of non-coding DNA leads to changes in expression of several different proteins. Although the genetic basis of myotonic dystrophy is now reasonably well understood, the contribution of molecular changes in the affected proteins to the myopathy has not been investigated. Our group has recently discovered that the juvenile form of the ryanodine receptor protein is highly expressed in adults suffering from myotonic dystrophy. By discovering more about the properties of the juvenile isoform, we will understand more about the basic mechanisms of ryanodine receptor function in developing muscle and in myotonic dystrophy and be able to design drugs to specifically modify ryanodine receptor activity.Read moreRead less
Structure Determination Of The Mammalian Ryanodine Receptor
Funder
National Health and Medical Research Council
Funding Amount
$377,397.00
Summary
Heart failure is the leading cause of death worldwide. We will determine the structure of the ryanodine receptor, a calcium channel involved in initiating contraction of cardiac and skeletal muscle. Detailed insights into the function of the ryanodine receptor will result from this work. An atomic structure of the cardiac ryanodine receptor will assist in the development of improved ryanodine receptor inhibitors to prevent and treat congestive heart failure.
Interactions Between The ? And ? Subunits Of The DHPR - A Missing Link In Skeletal Muscle Excitation-contraction Coupling And A Role In Sarcopenia
Funder
National Health and Medical Research Council
Funding Amount
$690,832.00
Summary
Calcium signaling is disrupted in muscle diseases, including muscle weakness in the elderly. This is a significant problem as all mobility depends on calcium signaling and its disruption can cause serious disability and death. To alleviate defective calcium signaling, the underlying molecular machinery must be fully understood, yet we have only a broad outline of the processes. We will address this problem to provide a platform for alleviating age-related muscle weakness.
Regulation Of Calcium Release Channels (RyR2) In Healthy And Failing Hearts
Funder
National Health and Medical Research Council
Funding Amount
$337,632.00
Summary
In striated muscle, the sarcoplasmic reticulum (SR) is the calcium store from which calcium release through ryanodine receptors (RyR2) is the key determinate of muscle force. We will develop an understanding of the complex functional changes in RyR2 that underlie adaptation of the heart to physiological stress (exercise) and functional changes associated with mal-adaptation in heart failure.
New Cardiac Ryanodine Receptor Inhibitors For The Treatment Of Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$612,885.00
Summary
We have discovered that a protein that is recognized for its role in phase II detoxification can also modify the calcium signaling that underlies heart function. The small part of the protein that is active in heart tissue differs from the enzyme center that supports detoxification and can thus be used as a therapeutic agent in heart failure and in genetic cardiac conditions. The project is to develop the cardio-active part of the protein for maximum efficacy and for eventual clinical use.
Communication Between Calcium Ion Channels In Skeletal Muscle Excitation-contraction Coupling
Funder
National Health and Medical Research Council
Funding Amount
$603,100.00
Summary
Ageing, injury, drugs or genetic defects cause muscle weakness, prevent exercise, compromise life style and contribute to poor health and osteoporosis. In order to move signals travel from our brain to muscles, where one calcium ion channel detects the signal and tells a second calcium channel to open and release calcium ions to initiate contraction. The project will pave the way for developing drugs to help with muscle disorders by trageting the site of interaction between the channels.
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