Development Of Therapeutically Useful Human Artificial Chromosomes For Gene Delivery And Optimal Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$496,986.00
Summary
Gene therapy is an exciting new form of treatment for genetic disorders aimed at providing long-term correction of the problems at source - namely the affected gene. The biggest technical hurdle facing gene therapy is to be able to deliver the therapeutic genes efficiently and safely into patient cells. Many gene therapy protocols are currently being trialled clinically. These protocols, based mostly on the use of attenuated viruses to deliver the genes, carry potential risks to the patients in ....Gene therapy is an exciting new form of treatment for genetic disorders aimed at providing long-term correction of the problems at source - namely the affected gene. The biggest technical hurdle facing gene therapy is to be able to deliver the therapeutic genes efficiently and safely into patient cells. Many gene therapy protocols are currently being trialled clinically. These protocols, based mostly on the use of attenuated viruses to deliver the genes, carry potential risks to the patients in terms of infection, immune response, and germline modification. We have developed the first stage of a new technology for gene delivery that does not require the use of viruses. This technology is based on the generation of human artificial chromosomes, which are smaller versions of the naturally occurring chromosomes that carry all the genes inside our cells. Safety in these artificial chromosomes comes from the use of entirely human materials for their engineering. These artificial chromosomes also have other advantages over the viral approaches, including allowing large genes to be carried, and providing a permanent cure in a single treatment. We have already successfully constructed, published, and patented a number of first-generation human artificial chromosomes. The current project aims to complete the next proof-of-concept milestone towards the further development of this technology. Specifically, we propose to demonstrate the ability of the artificial chromosomes to carry genes and provide sustainable expression of these genes in cells and in animal models. Success in this study will allow the technology to proceed rapidly into commercialisation and clinical trial as a new improved tool for gene delivery and gene therapy.Read moreRead less
Structural And Functional Analysis Of A Cancer-linked Co-regulator Complex
Funder
National Health and Medical Research Council
Funding Amount
$729,571.00
Summary
We seek to understand the mechanisms by which genes are switched on and off throughout our lifetime. A number of multi-component protein machines are involved in this process but their make-up and mechanism of action is not understood. We will investigate the structure and function of one of these machines that has been strongly linked to cancer.
Chromosomes are structures that carry genes in all our cells. Every human cell has 46 chromosomes. In the nucleus of eukaryotic cells, DNA is highly folded and compacted with specific proteins into a dynamic polymer called chromatin. Gene expression, chromosome division, DNA replication, and repair all act, not on DNA alone, but on this chromatin template. The discovery that enzymes can (re)organise chromatin into accessible and inaccessible configurations revealed mechanisms that considerably e ....Chromosomes are structures that carry genes in all our cells. Every human cell has 46 chromosomes. In the nucleus of eukaryotic cells, DNA is highly folded and compacted with specific proteins into a dynamic polymer called chromatin. Gene expression, chromosome division, DNA replication, and repair all act, not on DNA alone, but on this chromatin template. The discovery that enzymes can (re)organise chromatin into accessible and inaccessible configurations revealed mechanisms that considerably extend the information potential of the genetic code. In addition, it is now established that chromatin structural features can influence gene expression. In vitro studies support a model in which chromatin functions as a barrier for the access to DNA. Therefore this organization has to be tighly regulated and dynamic to allow the protein-DNA interactions critical for nuclear functions. Importantly genome organisation provides in addition to genetic information another layer of information, so called epigenetic, which by definition means that it is stably inherited throughout cellular divisions, yet it is not encoded genetically. Thus each cell type will display a specific epigenome. We have recently constructed small human minichromosomes, which are much easier to study than the much larger normal chromosomes. The present project proposes to define the epigenetic feature across an entire human chromosome using our minichhromosomes as working models. The outcome will be a significant gain in our knowledge on the processes underlying epigenetic regulation, the organisation of specialised chromatin domain, and behaviour of the chromosomes.Read moreRead less
The origins of electroreception and nocturnality in the earliest known jawed vertebrates and their bearing on vertebrate diversification. This project aims to discover primary new data to pinpoint the timing, anatomical origins and phylogenetic significance when two key sensory systems first appeared in modern vertebrates: electroreception and specialised nocturnal vision. Such abilities today allow high diversity of vertebrates to co-exist within the same geographical range, for example on trop ....The origins of electroreception and nocturnality in the earliest known jawed vertebrates and their bearing on vertebrate diversification. This project aims to discover primary new data to pinpoint the timing, anatomical origins and phylogenetic significance when two key sensory systems first appeared in modern vertebrates: electroreception and specialised nocturnal vision. Such abilities today allow high diversity of vertebrates to co-exist within the same geographical range, for example on tropical reefs or rainforest communities, through careful temporal niche partitioning where reliance on other sensory systems takes over from vision and olfaction as the principal method of prey detection. This project aims to elucidate how the modern fish diversity was shaped by such significant early evolutionary events.Read moreRead less
Resolving evolutionary problems at the fish-tetrapod transition. The project aims to investigate very early Australian tetrapod trackways and conduct fieldwork to resolve the place of origin and timing of the evolution of the first tetrapods. The evolution of fishes to tetrapods was one of the key events in evolution. Studies on Northern Hemisphere fossils place an origin for the group around 380 million years ago. Australian fossils suggest a much older origin. New micro computed tomography dat ....Resolving evolutionary problems at the fish-tetrapod transition. The project aims to investigate very early Australian tetrapod trackways and conduct fieldwork to resolve the place of origin and timing of the evolution of the first tetrapods. The evolution of fishes to tetrapods was one of the key events in evolution. Studies on Northern Hemisphere fossils place an origin for the group around 380 million years ago. Australian fossils suggest a much older origin. New micro computed tomography data from Australian 3-D fossil fishes, combined with study of rare tetrapod gill arch bones, would enable us to determine the origins of tetrapod air-breathing and its ecological setting. The project may facilitate a rewriting of vertebrate evolution's most significant first step.Read moreRead less
Violence, Religion and Well-being in Contemporary Burma (Myanmar): A Medical Anthropological Study of Everyday Life Under Dictatorship. For 40 years, Burma has been controlled by a military dictatorship with human rights abuses occurring daily. Terror and political violence are used as tools of repression. An in-depth ethnographic study will be conducted into the relationship between emotional/psychological distress and the violence and fear that pervades everyday Burmese life. The project will ....Violence, Religion and Well-being in Contemporary Burma (Myanmar): A Medical Anthropological Study of Everyday Life Under Dictatorship. For 40 years, Burma has been controlled by a military dictatorship with human rights abuses occurring daily. Terror and political violence are used as tools of repression. An in-depth ethnographic study will be conducted into the relationship between emotional/psychological distress and the violence and fear that pervades everyday Burmese life. The project will test the hypothesis that religion plays an important role in mediating responses to fear. No other study has been conducted of everday life under this dictatorship, or of survival strategies created to alleviate fear. Outcomes will include refereed articles, a major monograph on the subject and the development of a new methodology appropriate for aiding victims of terror and torture.Read moreRead less
Understanding Burma's Health Crisis and its Challenge to Regional Security: New Pathways to Peacebuilding. Researching ways in which war-torn societies can build the human capital necessary for long-term implementation of peacebuilding initiatives will contribute to making peace interventions more successful. The unique focus upon the right to health and its linkages with human rights within conflict economies will provide significant information and new policy directions for improving human sec ....Understanding Burma's Health Crisis and its Challenge to Regional Security: New Pathways to Peacebuilding. Researching ways in which war-torn societies can build the human capital necessary for long-term implementation of peacebuilding initiatives will contribute to making peace interventions more successful. The unique focus upon the right to health and its linkages with human rights within conflict economies will provide significant information and new policy directions for improving human security and stability among Australia's neighbours in the Asian region.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE150100026
Funder
Australian Research Council
Funding Amount
$379,536.00
Summary
Insect diversity and carrion decomposition in modified landscapes. Decomposition is fundamental to the recycling of nutrients in ecosystems, yet it is not known how different combinations of decomposer insects contribute to this important ecosystem service. This project includes a series of experiments to examine how insects affect carrion decomposition rates, and how this depends on environmental context. The project aims to show how decomposition is maintained in variable and changing landscap ....Insect diversity and carrion decomposition in modified landscapes. Decomposition is fundamental to the recycling of nutrients in ecosystems, yet it is not known how different combinations of decomposer insects contribute to this important ecosystem service. This project includes a series of experiments to examine how insects affect carrion decomposition rates, and how this depends on environmental context. The project aims to show how decomposition is maintained in variable and changing landscapes by revealing when the loss or gain of species will alter this critical ecological process. This will have implications for biodiversity-ecosystem function theory, and applications to biodiversity management and ecosystem restoration.Read moreRead less
ARC Centre for Kangaroo Genome. In this Australian-led Kangaroo Genome Project, we will map and characterize the tammar wallaby genome at the molecular level. Marsupial genomes are uniquely valuable because they provide comparisons that reveal new human genes, regulatory sequences and marsupial-specific genes. These will deliver new products and information useful for medicine, industry, agriculture and conservation. We will construct integrated genetic and physical maps of the genome, clone the ....ARC Centre for Kangaroo Genome. In this Australian-led Kangaroo Genome Project, we will map and characterize the tammar wallaby genome at the molecular level. Marsupial genomes are uniquely valuable because they provide comparisons that reveal new human genes, regulatory sequences and marsupial-specific genes. These will deliver new products and information useful for medicine, industry, agriculture and conservation. We will construct integrated genetic and physical maps of the genome, clone the whole genome as large inserts in BAC vectors, and build a "golden path" with minimal overlap. We will construct libraries of expressed genes from tammar tissues and array them for use in analysing gene expression.Read moreRead less
Genomic Analysis Of DNA Binding And Gene Regulation By The Chromatin Remodelling Factor UBF
Funder
National Health and Medical Research Council
Funding Amount
$624,254.00
Summary
Synthesis of ribosomes, the cellular protein synthetic machinery, is the major anabolic event of a growing cell and is frequently dysregulated during disease such as cancer. This grant will examine a protein termed UBF that we think plays an important role in orchestrating the cellular response to dysregulated ribosome biogenesis. By understanding how UBF functions we hope to uncover novel therapeutic approaches to treat diseases associated with ribosome stress .