MRNA Surveillance In Human Disease: Molecular Determinants Of Nonsense-mediated MRNA Decay
Funder
National Health and Medical Research Council
Funding Amount
$474,517.00
Summary
Inherited diseases are a common cause of human disability, illness and suffering. It has been estimated that 5-10% of the population will be affected by disorders with a genetic component. Thus studies on mechanisms of inherited diseases, especially those relating to genetic mechanisms with relevance across a wide range of individual disorders and gene mutations, are of great significance in diagnosis, molecular pathology and the eventual development of therapeutics. While there are many types o ....Inherited diseases are a common cause of human disability, illness and suffering. It has been estimated that 5-10% of the population will be affected by disorders with a genetic component. Thus studies on mechanisms of inherited diseases, especially those relating to genetic mechanisms with relevance across a wide range of individual disorders and gene mutations, are of great significance in diagnosis, molecular pathology and the eventual development of therapeutics. While there are many types of mutations, one relatively common type is called a premature termination mutation. Premature termination mutations introduce an inappropriate genetic signal that tells the cells to stop the formation of proteins before they are complete. This would result in the production of a protein that is shorter than normal, and these short proteins could be quite abnormal and drastically affect the normal function of cells. To overcome this, cells have developed elegant strategies that involve the deployment of quality control, or surveillance, mechanisms to remove the mutant gene product before it can be converted into an abnormal protein. This process is called nonsense mediated decay. Nonsense mediated decay is a complex process and some of the key components have been identified by studies on a small number of genes. However, our studies have identified several previously unknown aspects of the process that suggest that the currently held view of how nonsense mediated decay works is only the beginning of the story and further important complexity exists. The proposed research will explore the basic mechanisms of the surveillance process and determine the signals that initiate nonsense mediated decay. Since premature termination mutations cause one-third of all inherited genetic disorders, our studies will provide new insights into the surveillance mechanisms and will have wide applicability to our understanding of the basis of inherited disease.Read moreRead less
Elucidation Of Trafficking Of The Menkes (MNK;ATP7A) Copper-transporting ATPase In Epthelial Cells
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
Copper is an essential trace element for all organisms. Copper is needed for many processes including energy metabolism, the making and maintenance of strong bones and arteries with sufficient elasticity, the synthesis of chemical transmitters in the brain and for the reactions which remove toxic free radicals. Copper is also used by the proteins involved in important neurological diseases including Alzheimers disease and mad cow disease. Menkes disease is an inherited and usually lethal copper ....Copper is an essential trace element for all organisms. Copper is needed for many processes including energy metabolism, the making and maintenance of strong bones and arteries with sufficient elasticity, the synthesis of chemical transmitters in the brain and for the reactions which remove toxic free radicals. Copper is also used by the proteins involved in important neurological diseases including Alzheimers disease and mad cow disease. Menkes disease is an inherited and usually lethal copper deficiency disorder in humans, and the diverse and detrimental symptoms of this disease related to organs and tissues described above is a stark indicator of the essentiality of copper. We have carried out extensive research on Menkes disease and in particular the Menkes protein which in normal individuals plays a major role in maintaining the copper balance in cells, i.e. enough copper to satisfy nutritional needs of cells but not too much which causes toxicity. The normal Menkes protein catalyses the transport of copper across membranes of cells to the areas where it is needed by copper-dependent enzymes and is essential for copper absorption into the body from the gut. The normal Menkes protein functions as a molecular pump. We have discovered that this protein can sense copper concentrations in the cell and when these reach potentially toxic levels it can move (traffic) via small vesicles to the plasma membrane which surrounds cells. There it pumps the excess copper out of the cell and returns to its original location. Our studies are directed to understanding the molecular mechanisms which permit this remarkable protein to achieve a copper balance in living cells. The findings will be of major significance in understanding and treating acquired and inherited diseases involving copper deficiency or copper toxicity including osteoporosis, cardiovascular disease, and Alzheimer's disease.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0882382
Funder
Australian Research Council
Funding Amount
$245,000.00
Summary
Biophysical Characterisation Facility. The protein analysis facility will have substantial benefits for basic science and biotechnology. It will create capacity for South Australian researchers to study proteins at the biophysical level. The facility will support research projects within the designated national research priority areas of 'Frontier technologies for building and transforming Australian industries' and 'Promoting and maintaining good health
Molecular Investigations into Polyglutamine Repeat Proteins. The proposed research program, will provide significant fundamental insight into the processes that control protein aggregation and disease. Investigating processes central to protein aggregation is important, as it will further our understanding of these critically-important events and our understanding of disease processes. Such knowledge will increase Australia's international research standing, as well as having the potential to ....Molecular Investigations into Polyglutamine Repeat Proteins. The proposed research program, will provide significant fundamental insight into the processes that control protein aggregation and disease. Investigating processes central to protein aggregation is important, as it will further our understanding of these critically-important events and our understanding of disease processes. Such knowledge will increase Australia's international research standing, as well as having the potential to generate novel therapies, that prevent neurodegeneration.Read moreRead less
Analysing the detrimental effects of polyglutamine expansion. The proposed research program, will provide significant fundamental insight into the processes that control protein aggregation and its link with disease. Investigating processes central to protein aggregation is important as it will deepen our understanding of how proteins inappropriately change shape and our understanding of disease processes. Such knowledge will increase Australia's international research standing, as well as ha ....Analysing the detrimental effects of polyglutamine expansion. The proposed research program, will provide significant fundamental insight into the processes that control protein aggregation and its link with disease. Investigating processes central to protein aggregation is important as it will deepen our understanding of how proteins inappropriately change shape and our understanding of disease processes. Such knowledge will increase Australia's international research standing, as well as having the potential to generate novel therapies, that prevent neurodegeneration.Read moreRead less
New models of mitochondrial fatty acid oxidation disorders. Mitochondrial disease can affect both children and adults and is often fatal. This project will study mitochondrial function in cell types of the heart and brain to better understand how they generate energy in these tissues. This will provide new insights into mitochondrial metabolism and how defects in this process cause mitochondrial disease.
Characterisation of the novel mitochondrial protein (CABC1/ADCK3) and its role in protecting against oxidative stress. This is the first detailed characterisation and mechanistic study on a protein that protects against oxidative stress and neurodegeneration. Demonstrating the basis for this oxidative stress and its possible contribution to the cellular phenotype will be of benefit in understanding the disease process and ultimately designing approaches to minimise oxidative stress. An investiga ....Characterisation of the novel mitochondrial protein (CABC1/ADCK3) and its role in protecting against oxidative stress. This is the first detailed characterisation and mechanistic study on a protein that protects against oxidative stress and neurodegeneration. Demonstrating the basis for this oxidative stress and its possible contribution to the cellular phenotype will be of benefit in understanding the disease process and ultimately designing approaches to minimise oxidative stress. An investigation of this protein presents an opportunity for the investigator to work at the forefront in this field adding to Australia's scientific leadership in the area. It also represents an ideal project for post-graduate training and is a collaboration between groups in Brisbane and Melbourne. Read moreRead less
Development of a gene delivery system to access neuronal cells. Understanding the pathways for gene delivery and efficient expression will result in new knowledge in the areas of biotechnology and cell biology. This project will result in significant new information on vesicular trafficking pathways in neurons. An effective gene delivery system will realise significant commercial potential for our partner organisations and economic benefit to other Australian industry. This project aligns direct ....Development of a gene delivery system to access neuronal cells. Understanding the pathways for gene delivery and efficient expression will result in new knowledge in the areas of biotechnology and cell biology. This project will result in significant new information on vesicular trafficking pathways in neurons. An effective gene delivery system will realise significant commercial potential for our partner organisations and economic benefit to other Australian industry. This project aligns directly with the National Research Priority of "Promoting and maintaining good health" with a specific benefit for patients that suffer mental and physical degeneration and for their families.Read moreRead less
New Antioxidants Impacting on ROS and Free Radical Mediated Cellular Damage and Disease. Oxidative stress describes the condition where free radicals damage cells and biological systems and this stress underlies many diseases including neurological conditions and aging disorders such as Alzheimer's Disease. This project sets out to create new forms of powerful antioxidant drugs able to probe the mechanisms of such diseases with the view to developing new treatments and therapies.