SPECIFIC MODIFICATION OF SKELETAL MUSCLE RYANODINE RECEPTOR ACTIVITY
Funder
National Health and Medical Research Council
Funding Amount
$411,000.00
Summary
The project will have implications for muscle fatigue, which is a public health issue in an aging population, and for neuromuscular diseases and muscle weakness. The ryanodine receptor (RyR) calcium release channel regulates changes in calcium concentrations inside the muscle cell that are essential for respiration and movement. Defects in expression of RyRs results in death in utero or at birth. The RyR is also important in many other tissues, where it acts either alone or in combination with a ....The project will have implications for muscle fatigue, which is a public health issue in an aging population, and for neuromuscular diseases and muscle weakness. The ryanodine receptor (RyR) calcium release channel regulates changes in calcium concentrations inside the muscle cell that are essential for respiration and movement. Defects in expression of RyRs results in death in utero or at birth. The RyR is also important in many other tissues, where it acts either alone or in combination with a second type of calcium channel, to regulate the changes in the concentrations of calcium ions within the cell, which are essential for a variety of processes including cardiac contraction, vascular constriction, neuronal activity and immune responses. Despite its importance, little is known about the regulation of the RyR channel opening during contraction in skeletal muscle or the mechanisms of ion movement through its pore. It is often difficult to define the specific role of RyRs in intact tissues because of the lack of specific probes for the channel. The RyR is an obvious target for therapeutic drugs to modify muscle contraction, but has not been used as such because of the lack of specific and reversible drugs. Muscle performance is reduced, and fatigue is rapid, in neuromuscular disease. Performance can be improved by variety of drugs like anabolic steroids which unfortunately have additional adverse actions. The aims of the project are (a) to discover more about the regulation of, and ion conduction pathway through, the skeletal muscle RyR channel, (b) to identify compounds that can be used as specific probes for RyR activity and (c) to identify compounds that might in the future provide the basis for development of the RyR as a therapeutic target.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.
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.
DHPR ? Subunit Binding To A Variably Spliced Region Of RyR1: A Role In EC Coupling And Myotonic Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$555,892.00
Summary
We have uncovered a communication pathway between two ion channel molecules in muscle cells that underlies human movement. The pathway is critical in normal mobility and is disrupted in myotonic dystrophy. We will study the molecular components of this pathway to understand normal body function and abnormal function in mytotonic dystrophy. The work will facilitate the design of drugs to relieve the mytotonic dystrophy myopathy and form new and much needed class of specific muscle relaxants.
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.
A Novel Viral Modifier Of TNF Family Receptor Signalling: Elucidation Of Mechanisms Of Action
Funder
National Health and Medical Research Council
Funding Amount
$453,727.00
Summary
Over millions of years, viruses have evolved a great number of strategies to allow them to subvert the effectiveness of the host response. We have discovered that one of these viral strategies seems designed to block the synthesis of an important anti-viral factor, called tumour necrosis factor. In this project, we aim to work out how the viral factor blocks tumour necrosis factor production inside the cell, at the level of the molecules involved. The second aspect of this project concerns the i ....Over millions of years, viruses have evolved a great number of strategies to allow them to subvert the effectiveness of the host response. We have discovered that one of these viral strategies seems designed to block the synthesis of an important anti-viral factor, called tumour necrosis factor. In this project, we aim to work out how the viral factor blocks tumour necrosis factor production inside the cell, at the level of the molecules involved. The second aspect of this project concerns the identification of the types of cells and responses which the viral factor acts upon to manipulate the host response. We reason that this information will improve our understanding of how tumour necrosis factor production is regulated and the significance of this type of response in virus infection and physiology, more generally. The application of this research will be to aid the design of better drugs for the treatment of many conditions where tumour necrosis factor production contributes significantly to pathology, eg rheumatoid arthritis and autoimmunity. In some conditions, it may be a therapeutic advantage to selectively turn on tumour necrosis factor, eg for treatment of infections or cancer.Read moreRead less
Beyond access: women, higher education and the quiet revolutions of the 1950s. This project challenges the standard narrative of women in the 1950s through a study of the intersections of higher education, gender and place. By studying women graduates in Australia and the United States within the context of demographic, employment and cultural change, it develops life histories of graduate women over several decades of their post-universtiy lives, drawing on comparative sources. It offers a new ....Beyond access: women, higher education and the quiet revolutions of the 1950s. This project challenges the standard narrative of women in the 1950s through a study of the intersections of higher education, gender and place. By studying women graduates in Australia and the United States within the context of demographic, employment and cultural change, it develops life histories of graduate women over several decades of their post-universtiy lives, drawing on comparative sources. It offers a new framework for women's educational history, one that goes beyond access and focuses on the new identities that were formed as graduate women negotiated the contradictions of higher education and the dominant femininity of the period.Read moreRead less