The Role Of Heterochromatin In Regulating Cellular Proliferation And Development
Funder
National Health and Medical Research Council
Funding Amount
$504,000.00
Summary
Fundamental to the development of a multicellular organism is that for each cell type performing a specialised function, a different set of genes are turned on with the remainder being shut off. One of the most significant unanswered questions in biology is how a cell-type specific gene expression profile is established during early development. The answer to this question has important implications in understanding normal and abnormal cellular processes. Gene expression in a cell occurs in the ....Fundamental to the development of a multicellular organism is that for each cell type performing a specialised function, a different set of genes are turned on with the remainder being shut off. One of the most significant unanswered questions in biology is how a cell-type specific gene expression profile is established during early development. The answer to this question has important implications in understanding normal and abnormal cellular processes. Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free form but is covered with an equivalent weight of protein (histones) to form a structure known as chromatin. It has become clear that the chromatin structure encompassing a gene is the critical factor that determines whether a gene is expressed or silenced. We propose that developmental and cell-type specific mechanisms operate in a cell to assemble genes into highly specialised chromatin structures that permit (euchromatin) or restrict (heterochromatin) gene expression. In other words, the genome of each different cell type is organised into a unique and dynamic chromatin pattern and this pattern determines the gene expression profile. This investigation will show that the critical cellular mechanism that determines the chromatin pattern for a particular cell type is the regulation of the quantity and quality of heterochromatin. Specifically, we will demonstrate that this is achieved, in a developmental and tissue specific manner, by changing the make-up of chromosomal domains through the replacement of histone proteins with specialised forms of histones called variants . In addition, we will expose a new mechanism of how heterochromatin formation controls the rate of cellular proliferation. This information will provide new insights into how gene expression profiles are established at precise times in early development, and offer a new strategy to inhibit the proliferation of cancer cells.Read moreRead less
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
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
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
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
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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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