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The Tumour Cell-specific Nuclear Targeting Properties Of Chicken Anaemia Virus VP-3: Potential For Anti-tumour Therapy
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
Current trends indicate that cancer will cause 40% of all deaths in Australia by 2012, meaning that new anti-cancer strategies are urgently required. Our proposal intends to examine the subcellular targeting abilities of the unique tumour-cell specific agent apoptin (VP3 - viral protein 3), a small protein encoded by the genome of the chicken anaemia virus. Using various strategies, we have identified part of the apoptin molecule that confers efficient localisation in the nucleus of tumour cells ....Current trends indicate that cancer will cause 40% of all deaths in Australia by 2012, meaning that new anti-cancer strategies are urgently required. Our proposal intends to examine the subcellular targeting abilities of the unique tumour-cell specific agent apoptin (VP3 - viral protein 3), a small protein encoded by the genome of the chicken anaemia virus. Using various strategies, we have identified part of the apoptin molecule that confers efficient localisation in the nucleus of tumour cells, but not non-tumour cells. Our experimental program intends to define this tumour cell-specific targeting signal in detail, and determine the molecular basis of the differential subcellular localisation of apoptin in tumour compared to normal cells. This should contribute fundamental new information regarding the differences between cancer and normal cells. Additionally, we intend to optimise the targeting signal and perform initial experiments to test its efficacy in targeting anti-tumour drugs to the nucleus of tumour cells. Our long-term aim is to use the apoptin tumour cell-specific nuclear targeting signal as part of modular constructs to combat cancer efficiently, and above all, with minimal damage to normal cells and tissues.Read moreRead less
NUCLEAR AND TRANSGOLGI TARGETING AND MEMBRANE INDUCTION BY DENGUE NS5 RNA-DEPENDENT RNA POLYMERASE INTERDOMAIN REGION
Funder
National Health and Medical Research Council
Funding Amount
$450,750.00
Summary
Dengue virus is the causative agent of a mosquito-borne disease, Dengue fever, relevant to northern Queensland, where antibodies from a previous infection can complex with virus of a different serotype in a subsequent infection, and cause a severe, potentially fatal form of the disease (Dengue haemorrhagic fever-Dengue shock syndrome). The present proposal seeks to further understanding of the role of the dengue RNA-dependent RNA polymerase NS5, which is essential for viral RNA replication, with ....Dengue virus is the causative agent of a mosquito-borne disease, Dengue fever, relevant to northern Queensland, where antibodies from a previous infection can complex with virus of a different serotype in a subsequent infection, and cause a severe, potentially fatal form of the disease (Dengue haemorrhagic fever-Dengue shock syndrome). The present proposal seeks to further understanding of the role of the dengue RNA-dependent RNA polymerase NS5, which is essential for viral RNA replication, within the viral infectious cycle. We intend to examine the subcellular targeting properties of a short central region (the interdomain) of NS5, which appears to play multiple roles in targeting to both the perinuclear Golgi-membranes and to the nucleus, as well as in inducing intracellular membranes derived from the Golgi which are the site of viral replication. We will determine how NS5 localisation-membrane induction may differ in insect and primate cells, and attempt to isolate binding partners of NS5 from the nucleus and Golgi compartment of insect and primate cells using various different approaches. Our studies should assist in understanding NS5's critical role in the Dengue infectious cycle, and contribute towards devising new anti-viral strategies such as vaccination and-or therapies targeted at the NS5 interdomain.Read moreRead less
Risk Factors For Upper Limb Fractures In Children Falling From Playground Equipment - A Case Control Study
Funder
National Health and Medical Research Council
Funding Amount
$355,770.00
Summary
Each year in Victoria, up to 5,000 children attend hospital emergency departments with injuries associated with playground equipment. Approximately 1,000 children are admitted to hospital, reflecting the severity of these injuries. The estimated total lifetime treatment costs of these injuries is in the vicinity of $7.9 million (1996-97). In over three quarters of these children, a fall from equipment resulted in injury. Arm fracture is the most frequent and most costly injury. This study aims t ....Each year in Victoria, up to 5,000 children attend hospital emergency departments with injuries associated with playground equipment. Approximately 1,000 children are admitted to hospital, reflecting the severity of these injuries. The estimated total lifetime treatment costs of these injuries is in the vicinity of $7.9 million (1996-97). In over three quarters of these children, a fall from equipment resulted in injury. Arm fracture is the most frequent and most costly injury. This study aims to determine the factors which influence the risk of arm fracture in the event of a fall from playground equipment. It will focus in particular, on the height of the equipment and the type of undersurfacing. The study will involve interviewing children who have fallen from playground equipment at school or at pre-school. The results of the study will be used to make recommendations on how to improve the safety of playgrounds.Read moreRead less
Engineered Histones As DNA Carriers With Application In Therapeutic Gene Delivery
Funder
National Health and Medical Research Council
Funding Amount
$417,750.00
Summary
We intend to apply our knowledge of protein transport to the nucleus to enhance the delivery of DNA to target cells. This relates to the use of gene therapy to treat genetic defects such as inborn errors of metabolism, where a disease-causing lack-of-function mutation can be overcome by engineering cells within the organism which express, in the necessary quantities and in response to the appropriate regulatory signals, the particular component which is lacking. A limiting factor in gene therapy ....We intend to apply our knowledge of protein transport to the nucleus to enhance the delivery of DNA to target cells. This relates to the use of gene therapy to treat genetic defects such as inborn errors of metabolism, where a disease-causing lack-of-function mutation can be overcome by engineering cells within the organism which express, in the necessary quantities and in response to the appropriate regulatory signals, the particular component which is lacking. A limiting factor in gene therapy approaches is the low efficiency of nuclear uptake of introduced DNA, where it has been estimated that < 1% of the DNA taken up is actually expressed. Our proposal seeks to develop approaches to enhance non-viral-mediated gene delivery, in particular by optimising this critical, limiting step of the delivery of exogenous DNA to the nucleus. We intend to apply knowledge from studies of nuclear targeting and chromatin assembly to improve gene transfer technologies. We will build on our work showing that specific signals for nuclear import - nuclear targeting signals (NTSs) - can be used to enhance nuclear gene delivery and expression. Since DNA in the normal cellular context is in the form of chromatin - a specific complex with proteins such as histones - we intend to use reconstituted chromatin as the transfecting DNA, whereby histones engineered to include NTSs and other modular sequence elements will be used. Chromatin should not only enable NTSs and other sequence modules to be linked to the DNA but also protect against nuclease-mediated degradation prior to nuclear entry, condense the DNA to enable more efficient cellular-nuclear entry, and ensure expression of the transfected reporter gene by presenting it to the cell in a physiological context. Our approaches should contribute to bringing gene therapy closer to reality in the clinic.Read moreRead less
Role Of The Microtubule Network In Nuclear Transport: Potential Use In Gene Delivery
Funder
National Health and Medical Research Council
Funding Amount
$491,767.00
Summary
Transport of key proteins that regulate growth and other processes, into and out of the nucleus, the site of gene transcription, is central to the function of eukaryotic cells. Knowledge of the process is largely based on studies using semi-intact cell systems, however, meaning that the role of cytoskeletal elements in nuclear transport has been largely overlooked. Intriguingly, in vivo studies, including our own relating to signalling molecules important in the regulation of cancer, clearly imp ....Transport of key proteins that regulate growth and other processes, into and out of the nucleus, the site of gene transcription, is central to the function of eukaryotic cells. Knowledge of the process is largely based on studies using semi-intact cell systems, however, meaning that the role of cytoskeletal elements in nuclear transport has been largely overlooked. Intriguingly, in vivo studies, including our own relating to signalling molecules important in the regulation of cancer, clearly implicate the cellular microtubule (MT) network as playing an integral role in nuclear import. We propose to carry out a detailed examination of the mechanistic basis of the dependence of nuclear import on the MT network of 3 molecules regulating cancer. We will compare the properties of these molecules to those of other nuclear localizing molecules, as well as examine the ability to mediate nuclear import of similar MT-associating sequences from viral and other proteins. The results will establish for the first time, the generality of the dependence of nuclear protein import on cytoskeletal elements. Since the movement of large DNA molecules by simple diffusion is a limiting factor in non-viral gene delivery approaches, the possibility of applying this knowledge to facilitate the transport of DNA encoding therapeutic gene products to the nucleus of target cells, will also be assessed for the first time. We will use the modular sequences that confer interaction with the MT network to assist gene transfer by including them in modular constructs we have designed with this in mind. We will thus be able to test directly for the first time whether MT-interaction can enhance the delivery of DNA to the nucleus and reporter gene expression, with obvious application in gene therapy approaches.Read moreRead less
Drinking Patterns, Gender And Social Roles In Alcohol Problems In Victoria, In An International Comparative Context
Funder
National Health and Medical Research Council
Funding Amount
$342,239.00
Summary
The varied impacts of drinking in the family and other gendered relations are an important and understudied aspect of alcohol studies, with general social and policy implications. The proposed research will make an important contribution to developing quantitative research in this area in Australia. The project uses concepts and measures which are novel in an Australian environment, and the international comparative aspect of the project, with comparable questionnaires in a wide diversity of soc ....The varied impacts of drinking in the family and other gendered relations are an important and understudied aspect of alcohol studies, with general social and policy implications. The proposed research will make an important contribution to developing quantitative research in this area in Australia. The project uses concepts and measures which are novel in an Australian environment, and the international comparative aspect of the project, with comparable questionnaires in a wide diversity of societies, is novel and innovative for the alcohol research field in general. Measures of social problems from drinking, and particularly and family and relationship, developed in analysing the study material will be made more broadly available for use in future studies, raising the possibility that the study may serve as a first measurement point for future data-series over time.Read moreRead less
Effects Of Lead And Socio-cultural Factors On Cognition And Behaviour Of Children In Port Pirie And Broken Hill
Funder
National Health and Medical Research Council
Funding Amount
$394,825.00
Summary
The effect of lead on children's 'intelligence' is controversial. Poorer IQ scores in children with higher exposure to lead, have been found reasonably consistently, - but there is disagreement on whether lead exposure is simply a common ASSOCIATE of poor IQ, or whether it actually CAUSES deficits. In 1994, the NHMRC prudently recommended a graded series of interventions to be implemented, depending on the proprtion of children in the community with blood lead concentrations in specific categori ....The effect of lead on children's 'intelligence' is controversial. Poorer IQ scores in children with higher exposure to lead, have been found reasonably consistently, - but there is disagreement on whether lead exposure is simply a common ASSOCIATE of poor IQ, or whether it actually CAUSES deficits. In 1994, the NHMRC prudently recommended a graded series of interventions to be implemented, depending on the proprtion of children in the community with blood lead concentrations in specific categories above 10 ug lead -100 ml of blood. The choice of this figure (10 ug-dl) was more pragmatic than scientific; there being very little data on the health effects of exposures below 10 ug-dl available at that time. A recent analysis of pooled data from past studies has now suggested there may be very large effects on child IQ at blood lead concentration BELOW 10 ug-dl. Health authorities will soon be lobbied intensely to spend vast sums on new lead abatement programs. Cities like Port Pirie and Broken Hill (where cooperative programs have achieved such significant reductions in lead exposure that a high percentage of their children now have blood lead levels below 10 ug-dl), will be forced to examine expensive options to avoid closure of the industries which provide their economic backbones, if this analysis proves to be correct. Our proposal argues that before committing to new and costly abatement programs, there is an urgent need to augment our evidence-base by conducting a new study ofchildren with lead exposures below 10 ug-dl, using more modern measures of intelligence. The study will pay closer attention to some of the socio-cultural and inherited determinants of child IQ which may have confounded the lead-IQ association in past studies, and will supplement IQ assessments (which are now considered to derive from a very old and narrow view of intelligence) with new tools for measuring 'intelligence' that may be less socio-culturally dependent.Read moreRead less
Living In A Rural Community: A Longitudinal Study Of The Course And Outcome Of Mental Health And Wellbeing.
Funder
National Health and Medical Research Council
Funding Amount
$841,947.00
Summary
This unique rural Australian study will investigate individual, family and community factors associated with the mental health and wellbeing of residents in rural communities of New South Wales. It aims to identify factors that may maintain or promote mental health, thereby investigating the potential protective effect of community factors, as well as more proximal social factors (such as family-household attributes and responses) on dimensions of mental health and wellbeing among rural people.
Changing Heat: Direct Impacts Of Temperature On Health And Productivity - Current Risks And Climate Change Projections
Funder
National Health and Medical Research Council
Funding Amount
$277,915.00
Summary
We know that heatwaves kill people - some 50,000 died in the 2003 European heatwave - but little is known of the details. This project will discover those details, in three important dimensions: WHO is at risk, and where do they live; HOW are people at risk, e.g. from kidney failure; and just WHAT is it about heat that is most dangerous? We will then build mathematical models of the future risks, and explore what public health measures will best protect Australians in a warming climate.