The Role Of TRPM2 Channels In Oxidative Stress-induced Liver Damage
Funder
National Health and Medical Research Council
Funding Amount
$576,265.00
Summary
Oxidative stress plays a central role in liver injury induced by drug toxicity, ischemia-reperfusion, non-alcoholic fatty liver disease and viral hepatitis. A hallmark feature of oxidative-stress mediated hepatocellular death is Ca2+ and Na+ overload which suggest activation of ion channels on the plasma membrane. This project will investigate the role of Transient Receptor Potential Melastatine 2 (TRPM2) non-selective channels in oxidative stress-induced hepatocellular death.
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
Mitochondrial Dysfunction In Cardiac Hypertrophy And Failure
Funder
National Health and Medical Research Council
Funding Amount
$164,821.00
Summary
Heart failure is a disease of wide prevalence in the Western World. In addition to the human toll of heart failure, the economic impact is highly substantial. It remains unclear what causes heart failure, but the effects of calcium and free radicals produced in the mitochondria on muscle function are generally accepted as major contributors. The aim of this project is to understand how calcium and free radicals interact with each other and the mechanisms by which they reduce heart function.
Defining The Mechanisms That Control Exocytosis And Cell Signalling In Health And Disease.
Funder
National Health and Medical Research Council
Funding Amount
$473,477.00
Summary
This research focuses on pathways regulating nervous communication and hormone release. It centres on proteins that regulate this process and on the function of specific endocrine cells in health and disease. It uses unique research tools developed in this laboratory enabling the study of mechanisms regulating cell signalling. Through this research I aim to identify how the cells in our body communicate with each other and how this relates to diseases such as type 2 diabetes.
Hormone Transport By Alpha-2-Macroglobulin: Novel Roles In Regulating Hormone Activity
Funder
National Health and Medical Research Council
Funding Amount
$602,857.00
Summary
Alpha-2-macroglobulin is a large protein in the blood known to bind and transport numerous hormones in the circulation. Our previous studies published in BLOOD (2009) and JBC (2013) have discovered an important role for this molecule in the transport and regulation of a peptide hormone. The studies proposed in this application have important implications for understanding new roles of alpha-2-macroglobulin in hormone binding and regulating the activity of hormones in disease states.
Manipulating Store-operated Ca2+ Entry To Improve Muscle Function In Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$516,163.00
Summary
Muscle function is regulated in a complex manner by calcium and is impaired in Duchenne muscular dystrophy (DMD). Changes in calcium regulation will be investigated in DMD patients and in an animal model using a novel approach. We will use a combination of novel experimental approaches to manipulate muscles in dystrophic mice and test for improvement in function. Results will determine the viability of a potential treatment.
Role Of Nitric Oxide And Reactive Oxygen Species In Excitation-contraction Coupling In Skeletal Muscle.
Funder
National Health and Medical Research Council
Funding Amount
$163,250.00
Summary
Excitation-contraction (E-C) coupling is a term used to broadly describe the sequence of cellular events that starts with an electrical signal at the surface membrane of a muscle cell and which then ultimately leads to muscle contraction. Although the overall sequence is known, there remain many gaps in our understanding of the mechanisms involved not only related to normal muscle function but to how this function may be impaired by excessive exercise and disease. Many cellular metabolites contr ....Excitation-contraction (E-C) coupling is a term used to broadly describe the sequence of cellular events that starts with an electrical signal at the surface membrane of a muscle cell and which then ultimately leads to muscle contraction. Although the overall sequence is known, there remain many gaps in our understanding of the mechanisms involved not only related to normal muscle function but to how this function may be impaired by excessive exercise and disease. Many cellular metabolites contribute towards the normal control of muscle contraction, while others contribute to its impairment. Reactive oxygen species (ROS), which includes nitric oxide (NO) and related molecules, are metabolic factors often referred to as cellular oxidants. They are thought to have an essential role in controlling normal muscle function. Paradoxically, they are also implicated in the impairment of muscle function associated with fatigue, disease and aging. How these molecules both control normal muscle activity and also contribute to impairment of such function remains unclear. Thus, the central aim of this project is to identify the mechanisms by which the cellular oxidants, NO and other ROS, both control normal E-C coupling in skeletal muscle fibres and how they contribute to muscle fatigue. Clearly, understanding how skeletal muscle normally contracts is essential in order to better understand how muscle function can become impaired with exercise, disease and age. The work from this study will provide insight into both normal muscle physiology and how muscles fatigue and ultimately provide new methodologies and drugs that may combat fatigue, disease and age related changes to muscle function.Read moreRead less
Investigating Follistatin-based Interventions For Long Term-protection Against Frailty Associated With Chronic Illness And Aging
Funder
National Health and Medical Research Council
Funding Amount
$987,169.00
Summary
Effective therapies are urgently needed to combat frailty arising from muscle wasting associated with chronic illness and aging. The proposed studies will investigate the prospects of developing novel short-term interventions that can confer long-term benefits for preventing and treating muscle wasting associated with chronic illness and advanced aging.