Stochastic Modelling of Genetic Regulatory Networks: Subtitle - Genetic Regulation is a Noisy Business. The completion of the human genome marked the culmination of one hundred years of reductionist science in cell biology. Although further bioinformatics analysis will continue, the focus is shifting towards synthesis and understanding how the regulatory genetic components dynamically interact to form functional phenotypes. The key to this is the understanding of the roles of stochasticity in ....Stochastic Modelling of Genetic Regulatory Networks: Subtitle - Genetic Regulation is a Noisy Business. The completion of the human genome marked the culmination of one hundred years of reductionist science in cell biology. Although further bioinformatics analysis will continue, the focus is shifting towards synthesis and understanding how the regulatory genetic components dynamically interact to form functional phenotypes. The key to this is the understanding of the roles of stochasticity in cellular processes. This project will explore these roles and will develop an integrated complex systems modelling, simulation and visualisation framework. This will be used on an exemplar application for lineage commitment in haematopoiesis and for exploring and validating genetic regulatory models in general.Read moreRead less
Alternative Splicing in the Mouse Transcriptome. Although the human genome completion is cause for excitement we do not have any firm indication of precisely how many protein-coding genes exist in a mammalian genome. We have even less indication of the extent to which these genes generate alternative gene products, through a process termed alternative splicing. The detection and sequencing of these full-length alternative gene products is the focus of this application. This application details t ....Alternative Splicing in the Mouse Transcriptome. Although the human genome completion is cause for excitement we do not have any firm indication of precisely how many protein-coding genes exist in a mammalian genome. We have even less indication of the extent to which these genes generate alternative gene products, through a process termed alternative splicing. The detection and sequencing of these full-length alternative gene products is the focus of this application. This application details the opportunity to participate in the identification of the full transcriptome of the mouse and is part of a collaborative effort with The RIKEN Genome Sciences Center in Japan.Read moreRead less
Co-ordinated Action of ATM and DNA-PK in DNA damage recognition. The aim of this project is to investigate the mechanism of repair of double straind breaks in DNA sustained after radiation damage. Specifically we will focus on two proteins ATM (mutated in the genetic disorder ataxia-telangiectasia) and DNA-PK mutated in scid mice. There two proteins recognize double straind breaks in DNA and signal this damage to the DNA repair machinery of the cell and to cell cycle checkpoints. The emphasis ....Co-ordinated Action of ATM and DNA-PK in DNA damage recognition. The aim of this project is to investigate the mechanism of repair of double straind breaks in DNA sustained after radiation damage. Specifically we will focus on two proteins ATM (mutated in the genetic disorder ataxia-telangiectasia) and DNA-PK mutated in scid mice. There two proteins recognize double straind breaks in DNA and signal this damage to the DNA repair machinery of the cell and to cell cycle checkpoints. The emphasis here will be in the relationship between the two proteins in co-ordinating the repair of breaks in DNA. This information will be important in understanding mechanisms for maintaining the integrity of the genome.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
Investigating the role of gene loops in regulating gene expression. The ability to identify functional variants in regulatory elements will have implications for researchers in multiple fields of biology, from molecular medicine to agriculture. Transfer of expertise and application of the knowledge generated by our research to such fields stands to improve diagnosis of disease predisposition and to improve quality of animal and plant products. These outcomes will benefit all Australians. This kn ....Investigating the role of gene loops in regulating gene expression. The ability to identify functional variants in regulatory elements will have implications for researchers in multiple fields of biology, from molecular medicine to agriculture. Transfer of expertise and application of the knowledge generated by our research to such fields stands to improve diagnosis of disease predisposition and to improve quality of animal and plant products. These outcomes will benefit all Australians. This knowledge will also improve the education of Australian University students as it contributes to the development of advanced curricula and access to more powerful research methods. In addition, the project will foster important collaborations between Australian researchers and those overseas.Read moreRead less
ARC Centre in Bioinformatics. The Australian Centre for Genome-Phenome Bioinformatics will examine how the genome comes to life in the mammalian cell during differentiation and development. We will model, visualise and experimentally validate the complex cellular systems and regulatory networks that control the transformation of genomic information into biological structure and function. We will develop novel approaches and tools to improve health, optimise agricultural production and exploit ne ....ARC Centre in Bioinformatics. The Australian Centre for Genome-Phenome Bioinformatics will examine how the genome comes to life in the mammalian cell during differentiation and development. We will model, visualise and experimentally validate the complex cellular systems and regulatory networks that control the transformation of genomic information into biological structure and function. We will develop novel approaches and tools to improve health, optimise agricultural production and exploit new cell technologies. The Centre will build critical mass and national focus in bioinformatics to generate the human capital and intellectual property that Australia needs to compete in advanced bioscience and biotechnology.Read moreRead less
A new paradigm of gene regulation - implications in embryogenesis and disease. The proposed analysis of a new paradigm of gene regulation will provide a new key to understanding genome function and inform some of the most compelling biological issues of our time such as stem cell biology, tissue and organ regeneration and genetic programming. The insights and technologies developed in this program will be widely applicable in biotechnological and pharmacogenomic research in Australia and worldwi ....A new paradigm of gene regulation - implications in embryogenesis and disease. The proposed analysis of a new paradigm of gene regulation will provide a new key to understanding genome function and inform some of the most compelling biological issues of our time such as stem cell biology, tissue and organ regeneration and genetic programming. The insights and technologies developed in this program will be widely applicable in biotechnological and pharmacogenomic research in Australia and worldwide, and assert Australia's leadership in this area of research.Read moreRead less
Gene Expression Profiling and de novo Transcriptome Sequencing using Geneballs. The purpose of the project is to demonstrate that bead-based technology can be used in applications that currently require DNA hybridisation in order to overcome existing deficiencies in microarray technology. By providing the capability to quickly and efficiently produce, screen and utilize biomolecule libraries of nearly unlimited size, this technology provides the key to unlock the power of genomics and proteomics ....Gene Expression Profiling and de novo Transcriptome Sequencing using Geneballs. The purpose of the project is to demonstrate that bead-based technology can be used in applications that currently require DNA hybridisation in order to overcome existing deficiencies in microarray technology. By providing the capability to quickly and efficiently produce, screen and utilize biomolecule libraries of nearly unlimited size, this technology provides the key to unlock the power of genomics and proteomics for use in real world applications. The project has two aspects. First, relatively small directed cDNA-bead libraries will be compared to known low-density cDNA microarrays to validate the technique for utility in gene expression profiling. Secondly, large libraries containing short oligonucleotide sequences will be used for de novo sequencing of a complete transcriptome. Proof-of-concept in either case will pave the way for many genomic applications and catapult the technology to 'blockbuster' status.Read moreRead less
Organisation, expression and diversity of the sub-telomeric regions of the ancient eukaryote, Giardia duodenalis. We propose to extend our findings on the extreme plasticity of the structure and organisation of the sub-telomeric region of the complete genome of Giardia by more extensive chromosome walking, and comparison of different isolates. These regions are subject to gene conversion, transcriptional silencing, gene mobility, recombination, variable surface protein expression, subtelomeric i ....Organisation, expression and diversity of the sub-telomeric regions of the ancient eukaryote, Giardia duodenalis. We propose to extend our findings on the extreme plasticity of the structure and organisation of the sub-telomeric region of the complete genome of Giardia by more extensive chromosome walking, and comparison of different isolates. These regions are subject to gene conversion, transcriptional silencing, gene mobility, recombination, variable surface protein expression, subtelomeric instability and the insertion of transposable elements, a dynamic balance between structural conservation and rapid evolution. This is a rare opportunity to understand the forces at work in moulding eukaryotic sub-telomeric sequences because Giardia is not constrained by sexual homogenisation and the dynamic variability is retained.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