Characterisation Of A Novel Family Of Skeletal Muscle Gene Regulators
Funder
National Health and Medical Research Council
Funding Amount
$443,250.00
Summary
Muscle cells may be broadly divided into two classes, slow- or fast-twitch, with different physiological and biochemical properties. These properties are largely determined by the protein products of several multi-gene families that encode the contractile apparatus characteristic of muscle cells. The pattern of expression of these muscle-specific genes defines a muscle cell as either a slow-twitch or fast-twitch myofibre. Skeletal muscle is inherently plastic in its ability to express different ....Muscle cells may be broadly divided into two classes, slow- or fast-twitch, with different physiological and biochemical properties. These properties are largely determined by the protein products of several multi-gene families that encode the contractile apparatus characteristic of muscle cells. The pattern of expression of these muscle-specific genes defines a muscle cell as either a slow-twitch or fast-twitch myofibre. Skeletal muscle is inherently plastic in its ability to express different genes in response to altered functional demand, and under certain circumstances, fibres can convert from one type to another. Conditions known to cause myofibre conversion in humans include congenital myopathies, spinal injury, and exercise. We have identified a novel family of proteins that regulate the genes that confer fibre type. In this proposal, we will further characterise the function of each of these proteins in skeletal muscle development and fibre determination. In addition, the gene that encodes these proteins is one of many deleted in the human condition Williams-Beuren Syndrome (WBS). WBS is characterised by supravalvular aortic stenosis (SVAS), neurological and cognitive defects, infantile hypercalcemia, dental malformations, musculoskeletal anomalies and growth retardation with short stature. The musculoskeletal anomalies, including joint contractures, muscular pain and kyphoscoliosis, cause WS patients to lack stamina and fatigue easily. An underlying myopathy has been reported and may account for the physical limitations, however the disease causing gene-genes have not been identified. We predict that a lack of the MusTRD proteins contributes to these conditions. In general, the findings from our study will yield insights that will lead to improved treatments of patients who suffer from muscle disease or have sustained a nerve injury and improved approaches to excercise training.Read moreRead less
Restoring Skeletal Muscle In An Experimental Model Of COPD By Targeting The IGF-1-myostatin-macrophage Axis
Funder
National Health and Medical Research Council
Funding Amount
$508,183.00
Summary
Most people think that the serious disabilities of COPD (emphysema) patients follows damage to their lungs but wasted muscles may be even more important. We can not regrow lung but we have found a way that might help regrow muscle. We plan to use stem cells to make one of the body's own cells called 'macrophages' and genetically engineer these cells to help deliver healing proteins directly into the muscle. Making muscle stronger will help COPD patients live longer and improve quality of life.
Investigating Hippo Signalling As A Novel Cause Of Muscle Disease, And As A Target For New Interventions To Combat Frailty
Funder
National Health and Medical Research Council
Funding Amount
$460,509.00
Summary
We will explore the role of the Hippo signaling pathway in muscle development, repair and remodelling. We propose that this little-known pathway which affects organ development, is key for maintaining healthy muscles, and is affected in muscle wasting. Using gene therapy tools to alter this pathway in models of disease, we intend to clarify the role of Hippo signaling in muscle, and establish whether the pathway can be manipulated to treat physical frailty caused by muscle wasting.
THE ROLES OF CYTOSKELETAL PROTEINS IN SKELETAL MUSCLE FUNCTION AND DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$466,650.00
Summary
Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early chilhood and are characterised by poor muscle tone and muscle weakness. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, and myotubular myopathy. All of these disorders are characterised by disorganisation of the sarcomere, the major structure within skeletal muscle cells that is involved in contraction. In nemaline myopathy pat ....Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early chilhood and are characterised by poor muscle tone and muscle weakness. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, and myotubular myopathy. All of these disorders are characterised by disorganisation of the sarcomere, the major structure within skeletal muscle cells that is involved in contraction. In nemaline myopathy patients, mutations have been found in five genes that encode proteins of the filamentous systems of the sarcomere. Therefore, the genes for other thin filament, thick filament and Z-line proteins are excellent candidates for these disorders. Research from our lab has identified a novel region of the sarcomere and the genes encoding the proteins present in this region provide additional candidates for the congenital myopathies. We will further characterise the proteins in this novel structure to determine its function and the role that it plays in muscle disease pathologies. In order to study the relationship between disease pathology and muscle weakness in nemaline myopathy, we generated a mouse model by expressing a mutant protein, a-tropomyosin slow, found in human patients in mice. All features of the disease found in humans are present in the mice. A key feature of this disease in mice is the ability for muscle cells to grow in diameter or hypertrophy to offset the muscle weakness. We will use these mice to trial therapies including hypertropy-inducing agents, to prevent and reverse muscle weakness. In addition, we will generate an additional mouse model for this disease with a mutation in a gene encoding another filamentous protein. A comparison of the two models using microarray analysis will help us identify additional genes that are being affected in this disease and to generate a molecular expression profile that will aid in the diagnosis of this disease.Read moreRead less
Identification Of Novel Secretory Factors From The Heart As New Targets For Metabolic Disease
Funder
National Health and Medical Research Council
Funding Amount
$864,012.00
Summary
The incidence of obesity, type 2 diabetes and cardiovascular disease is rising at an alarming rate. The communication between the heart and distal tissues represents an exciting and emerging research area which has the potential to result in the identification of new targets and therapies. Here we will identify novel circulating proteins which could be developed as innovative therapies and ultimately translated into the clinic.
Novel Features And Mechanisms Of Congenital Myopathies
Funder
National Health and Medical Research Council
Funding Amount
$464,500.00
Summary
Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early childhood and are characterised by poor muscle tone and muscle weakness. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, and myotubular myopathy. All of these disorders are characterised by disorganisation of the sarcomere, the major structure within skeletal muscle cells that is involved in contraction. In addition, the congen ....Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early childhood and are characterised by poor muscle tone and muscle weakness. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, and myotubular myopathy. All of these disorders are characterised by disorganisation of the sarcomere, the major structure within skeletal muscle cells that is involved in contraction. In addition, the congenital myopathies have features in common with virtually all muscle diseases such as slow fibre predominance and alterations in contractile force. We are using nemaline myopathy as a representative congenital myopathy to examine features in common amongst the myopathies, characteristic of the congenital myopathies and specific to nemaline myopathy. In nemaline myopathy patients, mutations have been found in five genes that encode proteins of the filamentous systems of the sarcomere. A feature specific to nemaline myopathy is the presence of abnormal structures of the sarcomere called nemaline rods. We have analysed a large number of nemaline myopathy patients that have mutations in the genes that encode the filament proteins alpha-skeletal actin and tropomyosin. In addition, we have generated mouse models for nemaline myopathy and propose to generate an additional one with novel features. Our mouse model has revealed that a feature previously thought exclusive to dystrophies, is also present in nemaline myopathy. The combined analysis of well-characterised patient samples and mouse models will allow us to address longstanding questions about this particular congenital myopathy and myopathies in general. We will determine how rods form and their protein composition. Our mouse models in particular will allow us to address the molecular mechanisms that underpin the increase in slow twitch fibres and the effects that a particular mutation has on muscle function.Read moreRead less
Advancing The Diagnosis And Treatment Of Inherited Muscle Disorders
Funder
National Health and Medical Research Council
Funding Amount
$408,388.00
Summary
Inherited myopathies collectively affect ~1 in 1000 people, cause life-long disability and often shortened life. This fellowship addresses two key areas of need. 1. New gene discovery for the inherited myopathies using the latest genetic techniques and 2. developing therapies. I will test two recently developed drugs as potential treatments for tropomyosin myopathies and investigate key areas of disease mechanism for tropomyosin and RYR1 myopathies to identify new therapeutic targets.
Preclinical Testing Of 3 Cysteine-related Drugs For Reducing Dystropathology In The Mdx Mouse Model Of Duchenne Muscular Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$378,564.00
Summary
Duchenne muscular dystrophy (DMD) is devastating disease that affects young boys. We propose testing 3 cysteine related drugs which show promise in ameliorating the severity of the disease. The drugs are of particular interest because they are relatively inexpensive, can be taken orally, have few side effects and are already approved for human use. These drugs will tested in an animal model of DMD to test their efficacy.
Characterisation Of The Pathogenesis Of FHL1 Myopathies
Funder
National Health and Medical Research Council
Funding Amount
$748,652.00
Summary
Skeletal muscle is the most abundant tissue in the body and dynamically capable of responding to many environmental stresses. A key cellular process that has developed in muscle to facilitate adaptive responses is autophagy, a mechanism that facilitates the degradation and recycling of cellular debris. Defects in autophagy cause muscle disease. In this study we will identify a novel gene that regulates autophagy and will investigate how mutations in this gene cause muscle disease.