Disease Gene Discovery And Improved Genetic Diagnosis In Neuromuscular Disorders
Funder
National Health and Medical Research Council
Funding Amount
$473,321.00
Summary
Paediatric nerve and muscle disorders result in weakness, chronic disability and often early death. Over half of all affected children do not yet have a genetic diagnosis. This project will use advanced sequencing technology to increase genetic diagnosis rates and identify new disease-causing genes. This will result in improved patient care and a better understanding of the biological pathways altered by these disorders. It will also facilitate the identification of targets for future therapies.
Advancing Glycine To The Clinic For Duchenne Muscular Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$248,978.00
Summary
We have identified the therapeutic potential of the amino acid glycine for Duchenne muscular dystrophy (DMD), the most common and severe of the muscular dystrophies. To facilitate rapid translation to the clinic, this proposal will; 1) examine the effect of glycine on lifespan and quality of life in mouse models of DMD; 2) determine glycine’s mode of action; and 3) investigate whether these effects represent further benefits to those currently used gold standard treatments.
Therapeutic Potential Of Modulating Heat Shock Protein Expression For Muscle Wasting Disorder
Funder
National Health and Medical Research Council
Funding Amount
$1,172,146.00
Summary
Heat shock proteins help stressed proteins fold back to their original conformation and restore function. In a discovery published in Nature we identified induction of heat shock protein 72 (Hsp72) as a novel approach for muscular dystrophy and other conditions where there is inflammation and muscle weakness. This proposal will investigate whether Hsp72 induction is similarly effective in tackling the muscle wasting and weakness in conditions like ageing and frailty and in muscle injury.
We have designed novel gene therapy agents to treat MND. This therapeutic approach uniquely combines gene therapy agents with antibodies which stimulate motor neuron health and connections to muscle. This project will comprehensively characterise the therapeutic effects of our novel gene therapy agents in MND mice. We predict that our gene therapy complexes will improve motor neuron survival,motor function and lifespan in MND mice.
Maintenance of skeletal muscle integrity is critical for normal locomotor function. During adulthood skeletal muscle mass and strength is progressively lost which leads to locomotor impairment common in the elderly. Loss of skeletal muscle may also contribute to functional impairment in patients with inherited disorders of the scaffolding connective tissue that hold muscle fibres together, such as Duchenne's dystrophy. Understanding the biology of muscle cell growth and responses to environmenta ....Maintenance of skeletal muscle integrity is critical for normal locomotor function. During adulthood skeletal muscle mass and strength is progressively lost which leads to locomotor impairment common in the elderly. Loss of skeletal muscle may also contribute to functional impairment in patients with inherited disorders of the scaffolding connective tissue that hold muscle fibres together, such as Duchenne's dystrophy. Understanding the biology of muscle cell growth and responses to environmental stresses such as exercise and ageing is, therefore, critical to healthy daily functioning. In preliminary studies we have defined a novel biochemical pathway which we believe underlies the ability of muscle to grow larger and stronger. In this application, we propose to rigorously evaluate the role of this pathway in muscle growth by experiments performed both with cell culture models and in animals. The findings of this study would have direct therapeutic benefit for a large number of major clinical conditions, such as heart failure, age-related muscular weakness and muscle diseases.Read moreRead less
Molecular And Cellular Basis For Muscle Regeneration In Zebrafish.
Funder
National Health and Medical Research Council
Funding Amount
$541,104.00
Summary
Muscle repair occurs via the use of muscle stem cells, which provide skeletal muscle with its regenerative capacity. Muscle stem cells are particularly important in muscle diseases such as muscular dystrophies where muscle regeneration is an important factor in disease progression. We will identify the processes controlling muscle regeneration utilising zebrafish as a model organism. We hope this research will lead to an understanding of how muscle stem cells are generated.
The Pathogenesis Of Motor Neuron Degeneration Caused By A Triplet Repeat Expansion In The Androgen Receptor Gene.
Funder
National Health and Medical Research Council
Funding Amount
$284,748.00
Summary
Male sex hormones, or androgens, work by binding to a specific receptor, known as the androgen receptor. Androgens have an important and yet poorly understood role in nerve function. Our research is investigating how a genetic mutation in the androgen receptor causes Kennedy?s disease. This is a rare disease, affecting adult males, which causes nerves to die. The nerves which are affected are those supplying our muscles, called motor neurons. This leads to muscle wasting in the face and body. Ot ....Male sex hormones, or androgens, work by binding to a specific receptor, known as the androgen receptor. Androgens have an important and yet poorly understood role in nerve function. Our research is investigating how a genetic mutation in the androgen receptor causes Kennedy?s disease. This is a rare disease, affecting adult males, which causes nerves to die. The nerves which are affected are those supplying our muscles, called motor neurons. This leads to muscle wasting in the face and body. Other symptoms include testicular wasting, reduced fertility and breast tissue enlargement. It is currently not known what causes motor nerves to degenerate in Kennedy?s disease. We are endeavouring to investigate the cause of Kennedy?s disease via the generation of a transgenic mouse carrying this mutation. It is only through a studying transgenic mouse affected by this disease can we begin to understand what is happening to nerves to cause them to die, and importantly, how can we prevent them from dying. These studies will also provide crucial information on the effects of sex hormones on nerves. As there is currently no treatment for Kennedy?s disease, an aim of this project is to investigate how we can treat this disease. This will be the first time that we can systemically test potential treatments and work toward preventing the degeneration of these nerves. Kennedy?s disease is related to a number of other neurodegenerative diseases including Huntington?s disease, which are caused by similar genetic mutations. All of these diseases are caused by degeneration of specific nerve cells. Evidence suggests that there may be similar mechanisms involved in all of these diseases. The results of this study will therefore help us to understand a range of diseases and may eventually lead to the development of therapeutic strategies to prevent their debilitating effects.Read moreRead less
We have discovered a single tumour factor which causes cancer cachexia, a wasting condition that is one of the worst complications of malignancy, for which there is no current effective treatment. We have developed antibodies which effectively block this condition in preclinical models and have produced human/humanised version of this. This application is to characterise these human antibodies to allow us proceed to clinical trials.
Can Exercise Early After Spinal Cord Injury Prevent Deterioration Of Muscle And Bone?
Funder
National Health and Medical Research Council
Funding Amount
$775,049.00
Summary
Spinal cord injury leads to a profound deterioration of the muscles and bones in the paralysed limbs. This project will examine the effects of exercising the paralysed limbs as early as possible after injury to prevent muscle and bone loss rather than restoring the tissues once changes have occurred. The time course and mechanisms underlying the microstructural decay of bone over the first year after injury will also be examined to provide a basis for determining fracture risk in this group.