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Identification of functionally important autophosphorylation site(s) on ataxia telangiectasia and Rad 3 - related (ATR) protein kinase. The integrity of our genetic material must be maintained so that it can be passed on from one generation to the next and also to minimize the risk of cancer and other pathologies in an individual. There are multiple proteins involved in protecting our DNA including several enzymes that detect and signal DNA damage to a series of pathways involved in halting the ....Identification of functionally important autophosphorylation site(s) on ataxia telangiectasia and Rad 3 - related (ATR) protein kinase. The integrity of our genetic material must be maintained so that it can be passed on from one generation to the next and also to minimize the risk of cancer and other pathologies in an individual. There are multiple proteins involved in protecting our DNA including several enzymes that detect and signal DNA damage to a series of pathways involved in halting the passage of cells through the cell cycle so that repair can occur. This project studies the mechanism of action of one of these enzymes which will be of benefit in designing new compounds to fight disease. Read moreRead less
Novel mechanisms of bacterial arsenic metabolism - arsenate reduction and arsenite oxidation. Novel arsenic metabolising bacteria (i.e., arsenate respiring and arsenite oxidising), which are both phylogenetically and physiologically unique, have been isolated from arsenic-contaminated areas in Australia. The arsenate respiring bacterium, Chrysiogenes arsenatis, is of particular interest as it is the only organism reported able to respire with arsenate using the respiratory substrate acetate as t ....Novel mechanisms of bacterial arsenic metabolism - arsenate reduction and arsenite oxidation. Novel arsenic metabolising bacteria (i.e., arsenate respiring and arsenite oxidising), which are both phylogenetically and physiologically unique, have been isolated from arsenic-contaminated areas in Australia. The arsenate respiring bacterium, Chrysiogenes arsenatis, is of particular interest as it is the only organism reported able to respire with arsenate using the respiratory substrate acetate as the electron donor. It is proposed that physiological, biochemical and molecular biological studies be carried out to better understand the mechanisms by which these organisms metabolise arsenic. The knowledge gained from these studies will have worldwide application in the development of an arsenic bioremediation system.Read moreRead less
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
A novel role for SMG-1 protein kinase in stress granule formation and the stress response. Humans are constantly exposed to agents in the environment that threaten the integrity of their cells and increases the risk of cancer and other pathologies. Cells have developed repair mechanisms to cope with damage to their DNA and avoid long term effects. The emphasis in this application is to investigate the mechanisms by which stress affects the transcriptional machinery in the cell. A description of ....A novel role for SMG-1 protein kinase in stress granule formation and the stress response. Humans are constantly exposed to agents in the environment that threaten the integrity of their cells and increases the risk of cancer and other pathologies. Cells have developed repair mechanisms to cope with damage to their DNA and avoid long term effects. The emphasis in this application is to investigate the mechanisms by which stress affects the transcriptional machinery in the cell. A description of the processes involved will assist in understanding how specific disease states arise and will provide a means of devising compounds/drugs to assist the response to stress. Read moreRead less
Mechanism of higher-order chromatin formation and its role in controlling gene expression. The organization of genomic DNA into chromatin has solved one of the most difficult engineering problems required for the development of a multicellular organism; the compaction of over two meters DNA into a cell almost one millionth this size. Importantly, this compaction of the genome into chromatin has also been exploited by the cell to regulate the expression of genes. The aim of this investigation is ....Mechanism of higher-order chromatin formation and its role in controlling gene expression. The organization of genomic DNA into chromatin has solved one of the most difficult engineering problems required for the development of a multicellular organism; the compaction of over two meters DNA into a cell almost one millionth this size. Importantly, this compaction of the genome into chromatin has also been exploited by the cell to regulate the expression of genes. The aim of this investigation is to elucidate how genes are assembled into complex active or inactive chromatin structures by employing a novel in vitro system. This information will have important implications for gene therapy strategies.
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The Dynamic Control of Chromatin Structure. A human chromosome is a highly heterogeneous global structure because along its axis, it folds to different extents to form either highly compacted domains that repress the expression of genes or less condensed regions that enable genes to be turned on. Changes to the structure or stability of chromosomes, and the corresponding alterations to gene expression, have been linked to many diseases states like defects in human development and cancer. This s ....The Dynamic Control of Chromatin Structure. A human chromosome is a highly heterogeneous global structure because along its axis, it folds to different extents to form either highly compacted domains that repress the expression of genes or less condensed regions that enable genes to be turned on. Changes to the structure or stability of chromosomes, and the corresponding alterations to gene expression, have been linked to many diseases states like defects in human development and cancer. This study will uncover the underpinning mechanism of how our chromosomes are organised into distinct functional domains, which may offer the potential to develop new strategies to correct chromosomal abnormalities.
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Ribonucleic acid (RNA)-binding proteins regulate protein targeting and organelle biosynthesis. We will investigate a new paradigm in biology: the coordination of protein expression in space and time. Detailed knowledge will be gained about proteins that perform important roles in ensuring the proliferative potential of cells an essential aspect of stem cell biology, regenerative medicine and development of cancer. The study combines skills in several aspects of genetics, biochemistry and molecul ....Ribonucleic acid (RNA)-binding proteins regulate protein targeting and organelle biosynthesis. We will investigate a new paradigm in biology: the coordination of protein expression in space and time. Detailed knowledge will be gained about proteins that perform important roles in ensuring the proliferative potential of cells an essential aspect of stem cell biology, regenerative medicine and development of cancer. The study combines skills in several aspects of genetics, biochemistry and molecular cell biology and will therefore provide excellent training opportunities for PhD students and postdoctoral fellows in an internationally highly competitive field of research.Read moreRead less
Molecular mechanisms of stem cell self-renewal. Muscle growth and regeneration is critically dependent on its stem cell compartment. We have discovered that the p38 MAPK pathway is essential for stem cell self-renewal in the C2C12 myogenic cell line. This proposal seeks to understand the molecular basis of stem cell self-renewal in skeletal muscles, data that may be applicable to many stem cell systems, and to the enormous promise of stem cell therapies for injury and diseases of the aged. We wi ....Molecular mechanisms of stem cell self-renewal. Muscle growth and regeneration is critically dependent on its stem cell compartment. We have discovered that the p38 MAPK pathway is essential for stem cell self-renewal in the C2C12 myogenic cell line. This proposal seeks to understand the molecular basis of stem cell self-renewal in skeletal muscles, data that may be applicable to many stem cell systems, and to the enormous promise of stem cell therapies for injury and diseases of the aged. We will attempt to alter the balance of stem cell production by enforced p38 expression, and take microarray and proteomics approaches to define stem cell pathways.Read moreRead less
Preventing genetic damage with BIX - a novel player in the DNA damage response pathway. Defects in the DNA damage-response pathway underpin many human genetic disorders and diseases, including cancer. A detailed understanding of this process has enormous implications for future medicine. Our characterization of a novel protein involved in DNA damage signalling will help in screening inhibitors of this pathway that could be applied in chemo-and/or radiotherapy. This proposal will place Australia ....Preventing genetic damage with BIX - a novel player in the DNA damage response pathway. Defects in the DNA damage-response pathway underpin many human genetic disorders and diseases, including cancer. A detailed understanding of this process has enormous implications for future medicine. Our characterization of a novel protein involved in DNA damage signalling will help in screening inhibitors of this pathway that could be applied in chemo-and/or radiotherapy. This proposal will place Australia among the leaders in this internationally significant and highly competitive area of research leading to the creation of new compounds. Capture of this technology will create the opportunity for IP income, novel exports and new enterprises for Australia.Read moreRead less
Regulation of Stress Hormone Receptors in the Brain. Our research will provide information on how the brain controls our response to stress and will allow the development of targeted strategies to reduce the possibility during chronic stress of the development of conditions such as anxiety and depression. This will improve mental health outcomes in Australia and add to Australia's economic and social stability.