The role of intracellular calcium in fibre-type specific gene expression in skeletal muscle. Muscles contain different fibre types whose composition can be changed by activity. The aim of this proposal is to identify the intracellular mechanisms which control fibre type. Our hypothesis is that different patterns of intracellular calcium determine the pattern of gene expression which determines fibre type. Understanding how gene expression is regulated is a central issue in biology.
Regulatory mechanisms in skeletal muscle lipid hydrolysis. The regulation of intramuscular triglyceride (fat) utilisation by human skeletal muscle is largely unknown. Our contention is that the specialized protein enzyme, hormone sensitive lipase (HSL), has a fundamental role in intramuscular triacylglycerol utilisation and is regulated by both intramuscular levels of key metabolites and circulating hormone concentrations. We also propose control points subsequent to HSL activation are important ....Regulatory mechanisms in skeletal muscle lipid hydrolysis. The regulation of intramuscular triglyceride (fat) utilisation by human skeletal muscle is largely unknown. Our contention is that the specialized protein enzyme, hormone sensitive lipase (HSL), has a fundamental role in intramuscular triacylglycerol utilisation and is regulated by both intramuscular levels of key metabolites and circulating hormone concentrations. We also propose control points subsequent to HSL activation are important for triglyceride hydrolysis. Our proposed project examines these factors and will enhance our understanding of the regulation of muscle fat use, thereby leading to potential metabolic strategies (nutritional, pharmacological) that enhance skeletal muscle function at rest and during exercise.Read moreRead less
Biological Role of Contraction-Induced Heat Shock Protein Expression. It is well known that mammalian skeletal muscle increases its expression of a group of highly conserved proteins, the heat shock proteins (HSP) in response to repeated contraction. However, the biological role of this expression is unclear. The aim of this project is to determine the biological role of contraction-induced HSP expression. We expect to show that HSP synthesis in response to exercise has three major roles; 1) to ....Biological Role of Contraction-Induced Heat Shock Protein Expression. It is well known that mammalian skeletal muscle increases its expression of a group of highly conserved proteins, the heat shock proteins (HSP) in response to repeated contraction. However, the biological role of this expression is unclear. The aim of this project is to determine the biological role of contraction-induced HSP expression. We expect to show that HSP synthesis in response to exercise has three major roles; 1) to act to repair damaged proteins in recovery from muscle injury 2) to act as a "molecular motor" to translocate proteins from one region of a muscle cell to another and 3) to be released into the circulation in order to act as a central signal to activate immune cells. Such a project will be significant because it will allow for a fundamental understanding as to why these proteins are produced in response to exercise. We expect to enhance our understanding of fundamental cell biology.Read moreRead less
Reducing the fat burden: Identification of novel cellular and molecular targets for alleviating skeletal muscle insulin resistance. Insulin resistance and the associated consequences are a major public health problem in Australia and cost the healthcare system >$1.1 billion/year. Exercise training and thiaziolidinedione (TZD) treatment are therapies that partially ameliorate insulin resistance through distinct and independent mechanisms. However, neither intervention represents a viable long-ter ....Reducing the fat burden: Identification of novel cellular and molecular targets for alleviating skeletal muscle insulin resistance. Insulin resistance and the associated consequences are a major public health problem in Australia and cost the healthcare system >$1.1 billion/year. Exercise training and thiaziolidinedione (TZD) treatment are therapies that partially ameliorate insulin resistance through distinct and independent mechanisms. However, neither intervention represents a viable long-term strategy: exercise training has low compliance, while chronic TZD use is associated with several adverse side effects (edema, weight gain etc.). We will investigate the metabolic, cellular and molecular mechanisms by which these therapies each exert their positive effect on insulin action with the aim of identifying novel targets for future drug interventions. Read moreRead less
Intracellular localisation of insulin signalling proteins in human skeletal muscle following exercise. The metabolic action of insulin in skeletal muscle is enhanced by exercise, but the underlying mechanisms mediating this are unknown. Insulin receptor substrate proteins are key mediators in the intracellular insulin signalling pathway and play a central role in regulating many metabolic events. Our aim is to examine the hypothesis that exercise induces a novel subcellular redistribution of the ....Intracellular localisation of insulin signalling proteins in human skeletal muscle following exercise. The metabolic action of insulin in skeletal muscle is enhanced by exercise, but the underlying mechanisms mediating this are unknown. Insulin receptor substrate proteins are key mediators in the intracellular insulin signalling pathway and play a central role in regulating many metabolic events. Our aim is to examine the hypothesis that exercise induces a novel subcellular redistribution of these insulin receptor substrate proteins in skeletal muscle, such that the metabolic action of insulin is enhanced. Elucidating the mechanisms whereby exercise enhances insulin action underpins the development of new treatments and therapies with the aim of improving skeletal muscle function in health and disease.Read moreRead less
Impact of shear stress on vascular adaptations in humans. Large arteries are important for the delivery of blood and oxygen to organs such as the heart and brain. A primary physiological stimulus which controls the size and function of these crucial arteries is the magnitude of flow or, more accurately, shear force that the inner wall of the artery is exposed to. We have developed novel software which enables non-invasive assessment of arterial wall velocity, diameter and blood flow. We will ass ....Impact of shear stress on vascular adaptations in humans. Large arteries are important for the delivery of blood and oxygen to organs such as the heart and brain. A primary physiological stimulus which controls the size and function of these crucial arteries is the magnitude of flow or, more accurately, shear force that the inner wall of the artery is exposed to. We have developed novel software which enables non-invasive assessment of arterial wall velocity, diameter and blood flow. We will assess the impact of acute and chronic changes in wall flow and shear on arterial size and function. We will also develop new software which measures other aspects of artery wall behaviour. These basic human physiology studies have direct implications for assessment of artery health in humans.Read moreRead less
Environmental Control of Developmental Plasticity of Vertebrate Cardio-Pulmonary Systems. Our research will generate the first comprehensive picture of how environmental conditions are transduced to control the development of the vertebrate respiratory and cardiovascular systems over the perinatal period. The research will demonstrate how physiological systems are modified and hence evolve. Moreover, understanding the developmental pathology in embryos induced by changing environmental condition ....Environmental Control of Developmental Plasticity of Vertebrate Cardio-Pulmonary Systems. Our research will generate the first comprehensive picture of how environmental conditions are transduced to control the development of the vertebrate respiratory and cardiovascular systems over the perinatal period. The research will demonstrate how physiological systems are modified and hence evolve. Moreover, understanding the developmental pathology in embryos induced by changing environmental conditions (especially exposure to steroid-like pollutants) is crucial to support breeding programs of endangered species and may improve veterinary and medicinal treatment of premature animals and humans. This multi-disciplinary, international collaboration provides an international training ground and two-way exchange of students and postdocs.Read moreRead less
Coping With Pressure: Respiratory Biology of Marine Mammals. Many marine mammals undergo severe, protracted lung collapse during deep dives. They also exhibit prolonged periods of apnea during sleep. In humans, lung collapse and sleep apnea both represent severe respiratory dysfunction. Pulmonary surfactant, a complex mixture that lines the lung, stabilises the lungs in terrestrial mammals, preventing lung collapse. Here, we propose a comprehensive examination of respiratory function in marine m ....Coping With Pressure: Respiratory Biology of Marine Mammals. Many marine mammals undergo severe, protracted lung collapse during deep dives. They also exhibit prolonged periods of apnea during sleep. In humans, lung collapse and sleep apnea both represent severe respiratory dysfunction. Pulmonary surfactant, a complex mixture that lines the lung, stabilises the lungs in terrestrial mammals, preventing lung collapse. Here, we propose a comprehensive examination of respiratory function in marine mammals. This study will significantly advance our knowledge of the diving physiology of Australian marine mammals. A detailed examination of the respiratory and surfactant systems of marine mammals may also reveal adaptations that enable these animals to endure sleep apnea and lung collapse.Read moreRead less
Relaxin: molecular mechanisms of action in the reversal of fibrosis. Defects in relaxin and relaxin receptors are increasingly implicated as a cause of fibrosis which is associated with many disease processes. This study will examine the molecular mechanisms linking relaxin and fibrosis and will determine whether relaxin can be used to reverse the condition.
Brain temperature regulation in mammals: mechanisms and consequences. Mammals detect increases in body temperature predominantly in the brain. Counterintuitively many mammals selectively cool the brain during heat stress, which appears to defeat the mechanism for inducing cooling responses. We intend to investigate this apparent anomaly which we believe is concerned with optimizing water use in hot conditions. We will further investigate the source of water for evaporative cooling by panting and ....Brain temperature regulation in mammals: mechanisms and consequences. Mammals detect increases in body temperature predominantly in the brain. Counterintuitively many mammals selectively cool the brain during heat stress, which appears to defeat the mechanism for inducing cooling responses. We intend to investigate this apparent anomaly which we believe is concerned with optimizing water use in hot conditions. We will further investigate the source of water for evaporative cooling by panting and discover if there has been convergent evolution in thermoregulatory strategies in the eutherian and marsupial lineages. The data we collect will be used to support a new model for thermoregulation in mammals.
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