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
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
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
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 .
Regulation Of Ribosomal RNA Gene Chromatin During Malignant Transformation.
Funder
National Health and Medical Research Council
Funding Amount
$882,486.00
Summary
The overarching goal of this proposal is to determine the molecular basis for tumour cell dependence on activated ribosomal RNA gene repeats (rDNA). Our working model posits that rDNA repeats become activated through changes in rDNA chromatin structure that include increased binding of the RNA Polymerase I transcription factor UBF.
The Market for Technology in Australia. Over the last 5 years, formalised markets for technology have accelerated in the US. However, there is no recognised formal market in Australia. Results from our primary data collection and analysis will highlight whether deficiencies in the market for technology are creating obstacles for the commercialisation of Australian technology. This is a particularly important issue for Australia given our relative isolation arising from geographical distance and ....The Market for Technology in Australia. Over the last 5 years, formalised markets for technology have accelerated in the US. However, there is no recognised formal market in Australia. Results from our primary data collection and analysis will highlight whether deficiencies in the market for technology are creating obstacles for the commercialisation of Australian technology. This is a particularly important issue for Australia given our relative isolation arising from geographical distance and lack of attachment to a major trading bloc such as the EU or NAFTA.Read moreRead less
Mental health, job quality and workforce participation: evidence from population health research to address complex problems and conflicting policies. Mental disorders such as depression are a major cause of disability. Improving mental health can increase productivity and workforce participation. However, the psychosocial quality of work is a factor that overlays the relationship between work and health. Poor quality work (for example, unreasonable time pressure, insecurity) increases the risk ....Mental health, job quality and workforce participation: evidence from population health research to address complex problems and conflicting policies. Mental disorders such as depression are a major cause of disability. Improving mental health can increase productivity and workforce participation. However, the psychosocial quality of work is a factor that overlays the relationship between work and health. Poor quality work (for example, unreasonable time pressure, insecurity) increases the risk of poor mental health, absenteeism, and exit from the workforce. This project will analyse data following people over time to investigate the long-term health and employment consequences of poor psychosocial job quality, and consider the special case of mature age workers. It will identify those individuals at greatest risk, and factors that can buffer against the adverse effects of poor quality work.Read moreRead less
Working longer, staying healthy and keeping productive. Working longer, staying healthy and keeping productive. This project aims to develop a policy suite to respond to an older workforce. By 2060, nearly half of Australians aged 64 or older will be employed. Failure to address their health problems could threaten Australia’s economy, tax base and provision of health and care services. This collaboration between national policy portfolios (employment, social services, workplace health and socia ....Working longer, staying healthy and keeping productive. Working longer, staying healthy and keeping productive. This project aims to develop a policy suite to respond to an older workforce. By 2060, nearly half of Australians aged 64 or older will be employed. Failure to address their health problems could threaten Australia’s economy, tax base and provision of health and care services. This collaboration between national policy portfolios (employment, social services, workplace health and social equity) and expert scientists in work, health, social equality and policy process intends to reveal the diversity of older workers’ work-health dilemmas and effective ways for national policies to solve them. The policy suite will promote financial independence and meet social goals of equity and healthy ageing.Read moreRead less
Welfare receipt, demoralisation and mental health: how can welfare reform promote personal wellbeing and social inclusion? Welfare recipients are more likely to experience mental disorders and have poor wellbeing than non-recipients, and this can be a barrier to employment. This project examines the factors that may improve their mental health, promote employment outcomes, and help the Commonwealth Government develop effective welfare reform policies.