Ryanodine Receptor Inhibitors As Therapy For Ca2+ Store Overload Induced Arrhythmias
Funder
National Health and Medical Research Council
Funding Amount
$555,892.00
Summary
This study investigates a new therapeutic action recently discovered for flecainide, an antiarrhythmic agent that we find to completely prevent and inherited form of stress-induced arrhythmias called CPVT. The findings will provide the first detailed mechanistic understanding of an antiarrhythmic drug, findings that will also give a new direction for drug design to control common arrhythmias such as occur in diseases such as coronary artery disease.
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
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
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