Novel Transcriptional Regulation In Skeletal Muscle Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$344,592.00
Summary
It has been assumed that once genes are activated in a particular type of cell, they remain 'on'. From work described in this laboratory, we now know that gene activity may come and go. Instead of the analogy of a light switch that has been turned on and stays on, it appears that at least in muscle, gene activity is more like blinking lights. If you take an image of muscle tissue, which is just a snapshot in time, a gene may not appear to be activated if it was temporarily 'flashing off' at the ....It has been assumed that once genes are activated in a particular type of cell, they remain 'on'. From work described in this laboratory, we now know that gene activity may come and go. Instead of the analogy of a light switch that has been turned on and stays on, it appears that at least in muscle, gene activity is more like blinking lights. If you take an image of muscle tissue, which is just a snapshot in time, a gene may not appear to be activated if it was temporarily 'flashing off' at the time of viewing. This may occur in all tissue types, but it is more easily detected in muscle because the cell is large with many nuclei, rather than small with a single nucleus. Another reason why this phenomenon is more readily detectable in muscle cells is that they are very dynamic cells that can undergo fairly radical changes in shape. An actively growing or hypertrophying muscle cell may have all of its genes at a high pitch of transcriptional activity to support rapid growth. However, once a muscle cell has reached its appropriate size, then muscle genes switch to a flashing mode of transcription to maintain rather than build structures. SIGNIFICANCE: (1) This may be a fundamental mechanism of gene regulation that occurs in virtually all cell types. As such, our finding will open an area of research into the types of molecules involved in this novel mechanism. (2) Our studies will result in a better understanding of the mechanisms of muscle cell hypertrophy in response to excercise and drugs, as well as atrophy due to nerve damage or inherited muscle disease. (3) This mechanism may explain the expression of foreign DNA in muscle cells delivered via gene therapy approaches. Our findings could result in a more efficacious means of expressing the introduced gene that might require tricking the muscle fibre into believing that it is in a perpetual growth mode.Read moreRead less
Vascular Smooth Muscle Cell Senescence And The Effects Of Oestrogen
Funder
National Health and Medical Research Council
Funding Amount
$191,370.00
Summary
The incidence of cardiovascular diseases is much lower in women before menopause, and this is thought to be due to a beneficial effect of oestrogen on the cardiovascular system. However the mechanisms of the hormone’s cardiovascular-protective actions are still not clear. The proposed project will determine whether oestrogen acts by slowing the natural ageing process of cells.
Defining Mechanisms Of Follistatin-mediated Muscle Adaptation, For Treatment Of Frailty And Muscle-related Diseases
Funder
National Health and Medical Research Council
Funding Amount
$557,478.00
Summary
Physical frailty-weakness is one of the most common symptoms of serious illness and a key cause of death. I propose to study a new model of skeletal muscle growth, to learn more about the causes of wasting in muscle-related diseases. The work will identify cell mechanisms that cause loss of muscle strength, and will help develop novel treatment approaches to prevent or reverse physical frailty in illness. New therapies to combat frailty are vital to improve the health of our community.
Understanding The Mechanism Of Action And Pathophysiological Function Of The NOR1 And Nur77 Orphan Nuclear Receptors
Funder
National Health and Medical Research Council
Funding Amount
$269,250.00
Summary
Nuclear hormone receptors (NRs) function as ligand-hormone activated transcription factors that regulate gene expression involved in reproduction, development and metabolism. Dysfunctional hormonal signalling, and inappropriate NR function results in reproductive disorders, inflammation, cancer, diabetes, and cardiovascular disease. The significance of NRs in disease is underscored by the range of pharmacopoeia developed for the treatment of NR associated disorders. Orphan NRs belong to the supe ....Nuclear hormone receptors (NRs) function as ligand-hormone activated transcription factors that regulate gene expression involved in reproduction, development and metabolism. Dysfunctional hormonal signalling, and inappropriate NR function results in reproductive disorders, inflammation, cancer, diabetes, and cardiovascular disease. The significance of NRs in disease is underscored by the range of pharmacopoeia developed for the treatment of NR associated disorders. Orphan NRs belong to the superfamily on the basis of their sequence identity, however, the endogenous signaling molecules which bind to these proteins are unknown. The orphan NRs Nur77, NURR1, and NOR1, functions as stress response genes which are induced by a wide range of physiological stimuli Furthermore, the NR4A subgroup of receptors has been implicated in carcinogenesis, neurological disorders; inflammation, diabetes and atherogenesis. The objective of this proposal is to examine the molecular mechanisms that control the regulation of gene expression by the orphan nuclear receptors, Nur77 and NOR-1. Furthermore, we will investigate the pathophysiological function of NOR-1 and Nur77 in muscle. Nur77 and NOR-1 are expressed in skeletal muscle. This major mass tissue accounts for ~40% of total body weight and, is a major site of glucose and fat metabolism. Consequently, this peripheral tissue plays a significant role in insulin sensitivity, and the blood lipid profile. Furthermore, a collaboration with industry has identified NOR-1 as an insulin responsive gene in muscle, which becomes hyper-sensitive to insulin induction in diabetic patients. Additionally, we have exciting evidence that the anti-neoplastic purine anti-metabolite, 6-mercaptopurine activates the NR4A subgroup. Nur77 and NOR-1 represent an exciting challenge, and unlocking the molecular mechanisms that NOR-1-dependent transcription provides the opportunity for identifying novel signaling pathways, and therapeutics.Read moreRead less
The Role Of FHL Proteins In The Pathology Of Muscular Dystrophies: Identification Of Novel Therapeutic Targets
Funder
National Health and Medical Research Council
Funding Amount
$61,355.00
Summary
Scientists at Monash University have recently identified a protein called FHL1 which promotes skeletal muscle repair-growth and may reverse the muscle degeneration seen in inherited muscular dystrophies. This study will investigate whether FHL1 expression can improve muscle mass in mouse models of muscular dystropy. In doing so, this research improve out understanding of the molecular processes that cause muscular dystrophies and thereby lead the way to new therapies for this family of diseases.
REGULATION OF PROTEIN KINASES AND THEIR SUBSTRATES
Funder
National Health and Medical Research Council
Funding Amount
$1,296,159.00
Summary
Protein kinases are important regulatory enzymes involved in the control of virtually all physiological processes at the cellular level. The human genome is thought to contain approximately 1500 protein kinases to control these processes. These enzymes add phosphate groups to target proteins to modify their functions in a reversible manner with protein phosphatases removing the phosphate groups. This project is concerned with studying a metabolic stress sensing protein kinase called the AMP acti ....Protein kinases are important regulatory enzymes involved in the control of virtually all physiological processes at the cellular level. The human genome is thought to contain approximately 1500 protein kinases to control these processes. These enzymes add phosphate groups to target proteins to modify their functions in a reversible manner with protein phosphatases removing the phosphate groups. This project is concerned with studying a metabolic stress sensing protein kinase called the AMP activated protein kinase and its substrates. During periods of high energy demand such as vigorous exercise or nutrient stress induced by starvation or ischaemia the AMP activated protein kinase is responsible for shutting down energy requiring metabolic pathways and accelerating metabolism including glucose uptake and fatty acid metabolism to restore cellular energy levels. The AMP activated protein kinase regulates key enzymes in the control of cholesterol and lipid (fatty acid) synthesis as well as endothelial NO synthase, a key regulator of blood pressure and platelet activity. For these reasons it is potentially important in cardiovascular disease. The AMP activated protein kinase also appears responsible for exercise induced glucose uptake and it is known that exercise helps restore glucose control in age onset or type II diabetic patients. Since the AMP acitivated protein kinase accelerates fatty acid metabolism it may also have a role in obesity. While many factors are thought to be involved in cardiovascular disease, diabetes and obesity the AMP activated protein kinase is a key metabolic regulatory enzyme relevant to the most important diseases in Australia. Understanding the structure and function of the AMP activated protein kinase as well as the genes that encode this enzyme is an important goal.Read moreRead less
Understanding The Physiological Role Of COUP-TF Orphan Nuclear Receptors In Skeletal Muscle.
Funder
National Health and Medical Research Council
Funding Amount
$454,923.00
Summary
COUP-TF is a protein expressed in skeletal muscle, a tissue that accounts for ~40% of the body mass and energy expenditure, and is a major site of nutrient metabolism. COUP-TF is a member of the nuclear hormone receptor (NR) superfamily. These proteins respond to physiological signals, and are targets of pharmaceuticals for the treatment of inflammation, metabolic and endorcrine disorders. Our project is directed toward understanding the role of COUP-TF in the context of metabolism and obesity.
Controlling the concentration of calcium inside cells is extremely important for normal cell function. For example, a brief increase in calcium concentration inside muscle cells is essential for muscle contraction and the normal heart beat. This calcium is kept stored in sacs inside cells and is rapidly released when needed through calcium channels known as ryanodine receptors. We have discovered that some proteins (glutathione transferases and intracellular chloride channel proteins) inside cel ....Controlling the concentration of calcium inside cells is extremely important for normal cell function. For example, a brief increase in calcium concentration inside muscle cells is essential for muscle contraction and the normal heart beat. This calcium is kept stored in sacs inside cells and is rapidly released when needed through calcium channels known as ryanodine receptors. We have discovered that some proteins (glutathione transferases and intracellular chloride channel proteins) inside cells can affect how much calcium flows through these calcium channels. The proteins were thought to have other functions and our discovery of their effect on ryanodine receptor calcium channels has caused considerable excitement. We now plan to explore how they do this. We will mutate specific regions of the proteins to discover which regions are important and which are not. We will also look at whether closely related proteins have similar effects. The new class of ion channel modulator that we are studying has the capacity to alter not only respiration, movement and cardiac contraction, but also other aspects cardiovascular function, neuronal activity and immune responses. Understanding the way in which soluble proteins can interact with ion channels may reveal a novel target for drugs that affect ryanodine receptor calcium channel function and allow the rational design of specific drugs to regulate ion channels or ion channel modulators.Read moreRead less