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
Optimising the spring in your step to enhance footwear design. This project aims to examine how the nervous system adjusts the mechanical function of our feet across a spectrum of speeds, from slow running through to maximal effort sprinting. The proposed research will explore how the nervous system controls the function of the foot to meet the ever-varying demands of locomotion in the real-world. Expected outcomes of this project are to determine if running shoes help or hinder the natural spri ....Optimising the spring in your step to enhance footwear design. This project aims to examine how the nervous system adjusts the mechanical function of our feet across a spectrum of speeds, from slow running through to maximal effort sprinting. The proposed research will explore how the nervous system controls the function of the foot to meet the ever-varying demands of locomotion in the real-world. Expected outcomes of this project are to determine if running shoes help or hinder the natural spring-like function of the foot. It will explain a conceptually novel design allowing shoes to support our feet, whilst harnessing the energetic benefits of the foot's spring-like function. This research has the potential to revolutionise athletic footwear design and has direct implications for enhanced performance in running athletes.Read moreRead less
Growing up to be supersonic: bat echolocation origins and mechanics. This project aims to address the unresolved evolutionary origins of bat echolocation. Using a unique combination of development, evolution and novel engineering testing, this project expects to generate new insights into how features of the skull have evolved to allow bats to use their senses to interact with the environment. Expected outcomes include the identification of skull features that are unique to echolocating bats and ....Growing up to be supersonic: bat echolocation origins and mechanics. This project aims to address the unresolved evolutionary origins of bat echolocation. Using a unique combination of development, evolution and novel engineering testing, this project expects to generate new insights into how features of the skull have evolved to allow bats to use their senses to interact with the environment. Expected outcomes include the identification of skull features that are unique to echolocating bats and tests of how these relate to the frequency and detection range of sounds produced. Benefits include improved conservation planning for urban and rural bat populations, and potential commercial advances through engineering applications that mimic the biological process of echolocation. 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
A community based social identity approach to loneliness. Loneliness across Australia is a deep concern. Social prescribing is a novel community-based approach to managing loneliness, however it is unclear when and in what circumstances it is effective. This project aims to test a social identity approach to loneliness, incorporating longitudinal, cross-sectional, and experimental methods to understand how best to engage isolated people in group programs. The expected benefits of this project ar ....A community based social identity approach to loneliness. Loneliness across Australia is a deep concern. Social prescribing is a novel community-based approach to managing loneliness, however it is unclear when and in what circumstances it is effective. This project aims to test a social identity approach to loneliness, incorporating longitudinal, cross-sectional, and experimental methods to understand how best to engage isolated people in group programs. The expected benefits of this project are to produce a validated social prescribing model that can be implemented in multiple settings across Australia in order to reduce loneliness, strengthen communities, and guide more appropriate uses of health services.Read moreRead less
Improving Indigenous health and wellbeing over the family life course. Improving Indigenous health and wellbeing over the family life course. This project aims to reduce Indigenous health inequalities, a major social and economic problem, by improving the policy relevant evidence base on the determinants of Indigenous health and wellbeing. This project will compare the impact of the family life course on the health and wellbeing of Indigenous and non-Indigenous mothers and children. It will use ....Improving Indigenous health and wellbeing over the family life course. Improving Indigenous health and wellbeing over the family life course. This project aims to reduce Indigenous health inequalities, a major social and economic problem, by improving the policy relevant evidence base on the determinants of Indigenous health and wellbeing. This project will compare the impact of the family life course on the health and wellbeing of Indigenous and non-Indigenous mothers and children. It will use survey data that follows them over time to: 1) identify family structures that enhance or harm health and wellbeing, and; 2) track changes in health and wellbeing before, during and after family transitions (i.e. births, relationship changes). Anticipated results are better targeted policy interventions to reduce Indigenous health inequalities.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