The Role Of ERK MAPKs In Compensated Cardiac Hypertrophy
Funder
National Health and Medical Research Council
Funding Amount
$241,650.00
Summary
According to recent statistics, heart failure accounts for almost 300 deaths each year in Australia. In fact, heart failure is now a major health problem that is on the rise, despite the reduced incidence of other forms of heart and blood vessel disease. We are now in the situation where the cost of treatment of heart failure exceeds that of treating all cancer patients, and there are more patient days in hospital with heart failure than with any other heart or blood vessel disease. Most often, ....According to recent statistics, heart failure accounts for almost 300 deaths each year in Australia. In fact, heart failure is now a major health problem that is on the rise, despite the reduced incidence of other forms of heart and blood vessel disease. We are now in the situation where the cost of treatment of heart failure exceeds that of treating all cancer patients, and there are more patient days in hospital with heart failure than with any other heart or blood vessel disease. Most often, the heart fails to act as an effective pump following long-term exposure to high blood pressure. The increased work load placed on the heart effectively forces it to increase in size in a process called cardiac hypertrophy. But this initial compensation which is of benefit to the patient commonly deteriorates and many of the heart cells die. The resulting death of heart cells is the failure of the heart, and death of the patient is inevitable. The fundamental changes in the functional protein molecules of the heart cells that accompany hypertrophy and heart failure are likely to be extremely complex. As yet, no research has taken a global and unbiased look into this complexity. However, there are new technologies that allow us to take such a look. We have established a collaborative research team to investigate the fundamental mechanisms underlying cardiac hypertrophy. We are exploiting a novel model in which hypertrophy does not progress to failure. Our combined expertise allows us to use recently developed scientific methodologies to evaluate the biochemical basis for these events in the heart. We have chosen to focus on documenting the changes in proteins that accompany cardiac hypertrophy with the aim to establish important targets for interventions to permit cardiac cells to survive despite hypertrophy. This will have important implications for preventing cardiac failure.Read moreRead less
Regulators Of G Protein Signalling On The Golgi Complex
Funder
National Health and Medical Research Council
Funding Amount
$666,116.00
Summary
The secretion of proteins from cells involves a host of regulatory and signalling proteins. G proteins, signal transducers, located on the Golgi membranes, participate in the budding of transport vesicles in the secretory pathway. A newly-discovered family of Regulators of G Protein Signalling (RGS) proteins perform the critical function of turning off signals generated by G proteins. RGS proteins are powerful, but as yet, ill-defined regulatory molecules. In this study we will identify and char ....The secretion of proteins from cells involves a host of regulatory and signalling proteins. G proteins, signal transducers, located on the Golgi membranes, participate in the budding of transport vesicles in the secretory pathway. A newly-discovered family of Regulators of G Protein Signalling (RGS) proteins perform the critical function of turning off signals generated by G proteins. RGS proteins are powerful, but as yet, ill-defined regulatory molecules. In this study we will identify and characterize RGS proteins in macrophages that are located on Golgi membranes and help to regulate cytokine secretion and other immune functions. More detailed studies on selected RGS proteins will include mutational analysis of functional domains within the proteins and identification of other proteins that interact with RGS proteins. Overall these studies will lead us to understand how specific RGS proteins interact with G proteins and other molecules to regulate signalling in the secretory pathway. Anomalies in cell signalling have severe consequences in a variety of diseases and can cause cancer. Similarly, abnormal secretion in cells contributes to inflammation, diabetes and other disease processes. Information forthcoming from our studies on RGS proteins will have wide-reaching implications and the potential to reveal new targets for therapeutics in these diseases.Read moreRead less
Function Of The S100A1 Ca2+-binding Protein Under Physiological And Pathological Conditions
Funder
National Health and Medical Research Council
Funding Amount
$452,545.00
Summary
The S100A1 protein is one of the most abundant proteins in human heart muscle cells. It binds calcium ions and may play a role in the regulation of heart function. S100A1 levels are reduced in human heart failure, but it is unclear whether this reduction contributes to worsening of the disease. To study this, we have generated a genetically modified mouse strain that cannot make the S100A1 protein. We will use these mice to study how important the protein is for heart function under normal condi ....The S100A1 protein is one of the most abundant proteins in human heart muscle cells. It binds calcium ions and may play a role in the regulation of heart function. S100A1 levels are reduced in human heart failure, but it is unclear whether this reduction contributes to worsening of the disease. To study this, we have generated a genetically modified mouse strain that cannot make the S100A1 protein. We will use these mice to study how important the protein is for heart function under normal conditions, and how it contributes to the development of heart failure. Preliminary data indicate that adult mice with reduced S100A1 protein levels develop a form of heart disease that significantly reduces the efficiency of the pump function of the heart.Read moreRead less
Characterization Of Novel Regulators Of Erythropoiesis
Funder
National Health and Medical Research Council
Funding Amount
$437,545.00
Summary
Mature red and white blood cells develop from hemopoietic stem cells in the adult bone marrow. The production of red blood cells is primarily controlled by the hormone erythropoietin (epo). The availability of this hormone in a recombinant form has aided in the treatment of numerous forms of anaemia resulting from kidney failure, malignancies, and AIDS. Previously we had identified that the protein Lyn must be present inside primitive red blood cells for epo to stimulate them to become mature fu ....Mature red and white blood cells develop from hemopoietic stem cells in the adult bone marrow. The production of red blood cells is primarily controlled by the hormone erythropoietin (epo). The availability of this hormone in a recombinant form has aided in the treatment of numerous forms of anaemia resulting from kidney failure, malignancies, and AIDS. Previously we had identified that the protein Lyn must be present inside primitive red blood cells for epo to stimulate them to become mature functional cells. We have identified six molecules which interact with Lyn in red blood cells. We have shown that amolecule called HS1 is important for epo function in individual red blood cells and now we plan to investigate its functions in whole animals, including mice that lack the HS1 gene. We have also shown that a molecule called Trip1 is important for red blood cell development. Interestingly, this molecule also interacts with the thyroid hormone receptor and can influence the effects of epo and thyroid hormone on red blood cell development. The interplay between these two hormones will be looked at in more detail both at the cell and whole animal levels in normal mice and those lacking the thyroid hormone receptor gene. The third Lyn binding molecule we isolated is a novel gene-we have named it ankyrin repeat protein in line with the molecules it is related to. This gene is expressed in red blood cells and we aim to investigate what role it plays in the development of these cells. The fourth gene is also novel and is closely related to another called AFAP-110, which can exert effects on the structure of a cell. Its role in red blood cell structure will also be investigated. Finally, the last two molecule we have identified are both novel and are unrelated to any other known proteins. As above, the effects of these two molecules on red blood cell development will be investigated.Read moreRead less
Inside our cells is a complex traffic system. The vehicles are vesicles that come in different shapes and sizes and travel to specific destinations in the cell to deliver cargo such as: surface growth factor receptors that are to have their signalling terminated, proteins and lipids destined for the cell wall for growth or development (like neurite outgrowth) and proteins and hormones destined for secretion (like neurotransmitter release). More than 100 human genetic disorders map to defects in ....Inside our cells is a complex traffic system. The vehicles are vesicles that come in different shapes and sizes and travel to specific destinations in the cell to deliver cargo such as: surface growth factor receptors that are to have their signalling terminated, proteins and lipids destined for the cell wall for growth or development (like neurite outgrowth) and proteins and hormones destined for secretion (like neurotransmitter release). More than 100 human genetic disorders map to defects in one of the components of this system. Proteins called small GTPases provide order for this traffic and allow specific cargo to reach specific destinations. They regulate cell functions by acting as switches, turning biochemical processes on and off inside the cell. Ral is a small GTPase enzyme found in brain and broadly distributed in other cells. We have discovered that Ral is part of a large signalling complex. When activated Ral stimulates effectors, either the exocyst or RalBP1. In turn, mild oxidative stress controls a Ral inhibitor protein called ERp57. The research proposed aims to establish the functional role for the Ral signalling complex in cells. We will determine with which vesicle trafficking events Ral is associated, which effector it utilises in that pathway, and how that effector directs the traffic. We will also map the steps that may lead to inactivation of Ral via ERp57 in cells, and propose that this is mediated by mild oxidative stress. Techniques of molecular biology, biochemistry, molecular biology, proteomics and microscopy will be used to establish these functions. The research will lead to increased knowledge of the significance of this protein to cellular and particularly neuronal cell function. This forms the basis for understanding normal cell function and for identification of further factors causing diseases of vesicle transport. In time, such research aids in the development of specific therapies for sufferers of such diseases.Read moreRead less
E-cadherin is one of the major proteins responsible for mediating cell-to-cell adhesion in the body. During development, E-cadherin is essential for establishing the cellular architecture of epithelial organs and for maintaining epithelial function in the adult. In this context, E-cadherin acts to establish and maintain the polarity of epithelial cells. E-cadherin is also a powerful tumour suppressor and the loss of E-cadherin expression or function is a primary event in metastasis and cancer in ....E-cadherin is one of the major proteins responsible for mediating cell-to-cell adhesion in the body. During development, E-cadherin is essential for establishing the cellular architecture of epithelial organs and for maintaining epithelial function in the adult. In this context, E-cadherin acts to establish and maintain the polarity of epithelial cells. E-cadherin is also a powerful tumour suppressor and the loss of E-cadherin expression or function is a primary event in metastasis and cancer invasion. Proteins at the surface of epithelial cells must be sorted and trafficked, or transported, to different membrane domains. E-cadherin, for instance, must be trafficked to the lateral domain of cells in order to function in cell-cell adhesion. We recently discovered that cell surface E-cadherin is re-internalized and recycled back to the surface via a pathway that is poised to contribute to the regulation of cell adhesion. Our proposed studies aim to reveal how newly-synthesized E-cadherin and recycling E-cadherin are trafficked, which molecules and which vesicle carriers accomplish this transport. E-cadherin has specific amino acids that act as targeting signals for its sorting and trafficking; we have recently identified one such signal and will now seek the signal responsible for its endocytosis. Using specifically engineered mutants of E-cadherin we will also study other proteins that interact with E-cadherin during its trafficking for sorting and regulation. One of these is polycystin, a protein that is mutated in a common inherited kidney disease. Insights into this disease and normal kidney epithelial function will emerge from this work. A growing understanding of E-cadherin function and regulation is essential for the health of epithelial organs and for controlling and preventing cancer.Read moreRead less