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
TRANSCRIPTIONAL AND FUNCTIONAL CONSEQUENCES OF STAT3 ACTIVATION IN THE HEART
Funder
National Health and Medical Research Council
Funding Amount
$413,694.00
Summary
Recent statistics show that the disease known commonly as heart failure accounts for about 3000 deaths each year in Australia. Worldwide, a staggering 10 million people are thought to currently suffer from heart failure, with this number continuing to rise despite decreasing numbers of people suffering from other forms of heart and blood vessel disease. What causes a healthy heart to fail remains unclear, although in some circumstances failure is known to be initiated by genetic factors, viral f ....Recent statistics show that the disease known commonly as heart failure accounts for about 3000 deaths each year in Australia. Worldwide, a staggering 10 million people are thought to currently suffer from heart failure, with this number continuing to rise despite decreasing numbers of people suffering from other forms of heart and blood vessel disease. What causes a healthy heart to fail remains unclear, although in some circumstances failure is known to be initiated by genetic factors, viral factors, alcoholism, high blood pressure, or when the heart is damaged in a heart attack. We are interested in the molecular mechanisms that underlie the progression of the normal heart to failure. In 2003 we reported on altered signalling pathways in the failing human heart, and noted the increased phosphorylation of a spliceform of the transcription factor STAT3 in patients with heart failure. In this project, we will evaluate a larger group of heart failure patients for changes in phosphorylation of their STAT3 proteins. We will also increase the expression of an activated form of the STAT3 proteins in rat heart cells, and check whether there are accompanying changes in gene expression profiles that indicate a potential role in heart failure, or whether these cells are now predisposed to die. This will be extended with the use of transgenic animals (mice) engineered to overexpress activated STAT3 proteins. Again, we will focus on gene expression profiles. We will also evaluate whether the hearts of these animals are more likely to fail, either as the animals age, or when external stresses are experienced. With this information, we will be able to state whether STAT3 is a contributor to heart failure, and therefore whether it is an attractive target for future therapies aimed at reducing the morbidity and mortality of heart failure worldwide.Read moreRead less
The Coronary Vascular Bed, Shear Stress, Endothelial Signalling And Myocyte Electrophysiology
Funder
National Health and Medical Research Council
Funding Amount
$133,774.00
Summary
Physiologic control muscle performance includes a little understood signal from the walls of blood vessels stimulated by pressure and flow which effect muscle function. How this signal operates is controversial. We have developed a model which enables the evaluation of such signalling where changes in flow in the circumflex coronary artery induce easily measured local changes in electrophysiology which are confined to the territory of the circumflex coronary artery and which can be compared with ....Physiologic control muscle performance includes a little understood signal from the walls of blood vessels stimulated by pressure and flow which effect muscle function. How this signal operates is controversial. We have developed a model which enables the evaluation of such signalling where changes in flow in the circumflex coronary artery induce easily measured local changes in electrophysiology which are confined to the territory of the circumflex coronary artery and which can be compared with control values from the left anterior descending coronary artery territory. We propose to use this stable model to evaluate the origin, the transmission agent and the mechanism by which it alters the action potential duration.Read moreRead less
Making Human T- And B-lymphocytes For Immunotherapy And Antibody Production
Funder
National Health and Medical Research Council
Funding Amount
$795,880.00
Summary
Lymphocytes are white blood cells that are involved in producing antibodies, killing defective cells, or killing cells infected with viruses. In recent years, researchers have found ways to harness lymphocytes to develop medicines for treating a variety of different cancers. In this project, we will establish methods to make human lymphocytes in the laboratory from stem cells, paving the way for the broader application of this cell type to new therapies.
Regionalisation And Differentiation Of EPL-derived Neurectoderm: Directed Formation Of Dopaminergic Neurons In Vitro.
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Neurodegenerative diseases result from the loss, damage or dysfunction of neural populations. For example, dopaminergic neurons are lost progressively in Parkinson's Disease. A potential method of treatment is 'cell therapy' which envisages transplantation of cells back to the site of cell loss, and restoration of function. Application of the cell therapy approach is limited by the unavailability of cells for transplantation. Embryonic stem (ES) cells provide a potential solution to this problem ....Neurodegenerative diseases result from the loss, damage or dysfunction of neural populations. For example, dopaminergic neurons are lost progressively in Parkinson's Disease. A potential method of treatment is 'cell therapy' which envisages transplantation of cells back to the site of cell loss, and restoration of function. Application of the cell therapy approach is limited by the unavailability of cells for transplantation. Embryonic stem (ES) cells provide a potential solution to this problem because they can be grown in unlimited numbers and differentiated to any kind of cell that is found in the embryo or adult. In this application we propose to continue our work on controlling the differentiation of ES cells to neural lineages. Production of dopaminergic neurons will be a particular focus. We will establish conditions that enable the production of these cells in a manner that is therapeutically relevant and predicted to be acceptable to regulatory authorities. Cells will be tested by transplantation into adult rats to assess their therapeutic potential, in particular persistence, integration and differentiation within the brain environment. Research required to achieve the production of transplantable cells will also provide basic information about the mechanisms by which the mammalian embryo allocates cells, specifically cells of the nervous system, to specific lineages during embryogenesis. This information will be important for the production of other neural cell types, which have therapeutic potential for treatment of diseases like stroke, motor neuron disease and spinal cord injury.Read moreRead less
Analysis Of T Cell Fate Regulation By Asymmetric Cell Division
Funder
National Health and Medical Research Council
Funding Amount
$287,321.00
Summary
The aim of this research is to study how white blood cell growth is regulated by signals of the immune system. Problems in this process can have drastic effects on the well being of an individual leading to deficiencies in controlling infection and development of diseases such as cancer. Once we understand how these signals regulate white blood cell growth, we can begin to develop therapies to provide protection against these diseases.