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GENETIC PREDICTION OF FRACTURE IN A RISK-STRATIFIED POPULATION
Funder
National Health and Medical Research Council
Funding Amount
$363,000.00
Summary
Osteoporosis is a condition characterised by excessive bone loss and impaired bone quality, which ultimately results in fracture with minimal trauma. Osteoporosis affects 27% of women and 11% of men aged 60 years or above in the community, and costs Australia around $7 billion each year. Individuals with low bone mineral density (BMD) have a significantly higher risk of fracture than those with normal BMD. In the long-term (14-year) Dubbo Osteoporosis Epidemiology Study, more than half of indivi ....Osteoporosis is a condition characterised by excessive bone loss and impaired bone quality, which ultimately results in fracture with minimal trauma. Osteoporosis affects 27% of women and 11% of men aged 60 years or above in the community, and costs Australia around $7 billion each year. Individuals with low bone mineral density (BMD) have a significantly higher risk of fracture than those with normal BMD. In the long-term (14-year) Dubbo Osteoporosis Epidemiology Study, more than half of individuals with osteoporosis (e.g., low BMD) did not sustain a fracture, while approximately 60% of fracture cases had BMD above the high risk levels. Thus, BMD alone is not a good discriminant of fracture versus non-fracture cases. It is widely known that the liability to fracture is determined in part by genes. Previous studies, including from our group, have suggested a number of candidate genes that are associated with fracture risk. The fundamental issue that this study is concerned is that how and whether genetic markers could be used to facilitate case finding. It is proposed that common variations of certain genes are associated with fracture risk independent of BMD. That is, they can identify individuals at relatively high and low fracture risk after stratification for BMD. Hence, some markers may identify those individuals likely (and unlikely) to fracture even with low (osteoporotic) BMD. Similarly, some, possibly the same, markers may identify individuals at high risk of fracture despite relatively good (ie non-osteoporotic) BMD. It is further proposed that no single gene will achieve this outcome, but rather a small set of such gene polymorphisms will provide clinically useful risk information. This effect is entirely analogous to the use of clinical risk indicators (eg, age, weight, sex, family history, etc) to assess the risk of future fracture.Read moreRead less
THE EFFECTS OF TRANSCRANIAL MAGNETIC STIMULATION (TMS) ON RAT MODELS OF DEPRESSION
Funder
National Health and Medical Research Council
Funding Amount
$204,274.00
Summary
Repetitive Transcranial Magnetic Stimulation (rTMS) is the direct stimulation of the brain by using high field magnetic pulses. It is a new technique that has been demonstrated to have some potential as a treatment of depressive illness and possibly other neuropsychiatric disorders. At this early stage of its investigation, the parameters of stimulation that are most likely to be therapeutic, and its mechanisms of action, are not known. Published studies vary in the frequency, duration and exten ....Repetitive Transcranial Magnetic Stimulation (rTMS) is the direct stimulation of the brain by using high field magnetic pulses. It is a new technique that has been demonstrated to have some potential as a treatment of depressive illness and possibly other neuropsychiatric disorders. At this early stage of its investigation, the parameters of stimulation that are most likely to be therapeutic, and its mechanisms of action, are not known. Published studies vary in the frequency, duration and extent of stimulation, with no firm guidelines about optimal parameters. Empirical study of the relative effects of stimulation at different frequencies, at different numbers of stimuli and for different durations is therefore important for the future development of this treatment. Such an investigation is best carried out in an animal model of depression for both ethical and practical reasons, as such studies in patients would possibly take many years and be extremely difficult to conduct. We propose such a study in rat models of depression which have demonstrated validity and utility in drug research. Rat models have a long track record in developing psychiatric treatments and are cost-effective and of proven value. We also plan to investigate the neuroanatomy of the immediate-early genes induced by TMS and compare it with electroconvulsive shock (ECS) and a tricyclic antidepressant, two established treatments of depression. The results will have implications for future human studies in guiding us toward the optimal parameters for therapeutic effects. They will also enhance our understanding of the mechanism of action of TMS in depression.Read moreRead less
Role Of IGF Binding Protein-3 (IGFBP-3) And IGFBP-5 As Modulators Of Nuclear Hormone Signalling
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
The insulin-like growth factors are small proteins involved in the growth of most tissues. Their actions are regulated by binding to larger proteins (known as IGFBPs) in the bloodstream and outside the cell. However, some IGFBPs are also found inside cells, where they seem to carry out other functions. We believe that two of these binding proteins, IGFBP-3 and IGFBP-5, change the way cells respond to vitamin A and vitamin D. These two vitamins are important in cell growth and in the way certain ....The insulin-like growth factors are small proteins involved in the growth of most tissues. Their actions are regulated by binding to larger proteins (known as IGFBPs) in the bloodstream and outside the cell. However, some IGFBPs are also found inside cells, where they seem to carry out other functions. We believe that two of these binding proteins, IGFBP-3 and IGFBP-5, change the way cells respond to vitamin A and vitamin D. These two vitamins are important in cell growth and in the way certain cells perform specialised functions. In test-tube experiments, IGFBP-3 and IGFBP-5 interact directly with the receptors that regulate the effects of these hormones. If the same thing happens inside the cell, IGFBP-3 and IGFBP-5 could change the way these receptors respond to signals from outside the cell. We will investigate what effect these IGFBPs have in living cells and in whole animals and how this may relate to human disease. If we are able to understand how IGFBP-3 and IGFBP-5 affect the way cells respond to vitamin A and D, then we may be able to develop new ways to treat certain human diseases.Read moreRead less
Identification Of Heterogeneity In Vasodilator Function In Human And Rat Resistance Vessels: Potential Drug Targets?
Funder
National Health and Medical Research Council
Funding Amount
$595,330.00
Summary
The balance between the ways that blood vessels decrease in size (constrict) and increase in size (dilate) determine how blood vessels normally function. There are many differences in the ways that blood vessels control this balance in different parts of the body. Such differences are altered in vascular diseases, such as hypertension and diabetes, which are prevalent in obesity, such that constriction generally outweighs dilation. However, what these differences are and how they occur are not w ....The balance between the ways that blood vessels decrease in size (constrict) and increase in size (dilate) determine how blood vessels normally function. There are many differences in the ways that blood vessels control this balance in different parts of the body. Such differences are altered in vascular diseases, such as hypertension and diabetes, which are prevalent in obesity, such that constriction generally outweighs dilation. However, what these differences are and how they occur are not well understood. While current drugs for treating vascular disease either reduce vessel constriction or increase dilation, they are not specific for individual arteries; a situation that would allow us to control vascular diseases in a very specific manner. Recently, we have described differences between the ways that individual vessels are controlled. These changes relate to differences in the way that different vessels dilate. AIMS - To further understand normal blood vessel function and the changes that occur in blood vessels in cardiovascular disease, with a focus on the ways that blood vessels dilate in normal states and in obesity-related diseases, such as in hypertension and diabetes. - The eventual aim is to identify the specific ways that arteries function, so that artery-specific drug targets can be identified to treat disease-related changes in cardiovascular disease in a very specific manner. EXPECTED OUTCOMES This project will contribute to understanding blood vessel function in health and disease. The expected eventual outcome is the identification of the mechanisms that underlie the function of different arteries in different parts of the body, so that specific individual vessel function can be targeted to treat vascular disease. Additionally, this work will also verify the relevance of the diet-induced obesity animal model, in terms of the characteristics and causes of human obesity and related cardiovascular disease.Read moreRead less
A Randomised Controlled Trial Of Caseload Midwifery Care
Funder
National Health and Medical Research Council
Funding Amount
$761,311.00
Summary
There is concern about the rising levels of caesarean section in Australia and some evidence that women may benefit from caseload midwifery care. This randomised control trial will determine whether caseload midwifery care can reduce interventions and is as safe as usual hospital maternity care. A Cochrane systematic review of midwifery led care versus routine care was designed to answer these questions.This will be the first randomised controlled trial to contribute to this review
A Randomised Control Trial Of Non-specific Clinical Management Versus CBT In Chronic Anorexia Nervosa
Funder
National Health and Medical Research Council
Funding Amount
$555,843.00
Summary
Anorexia nervosa (AN) is a serious mental illness that usually starts in adolescence and often runs a chronic course. With an estimated prevalence rate between 0.5% and 3.7% of women, and up to 50% remaining chronically ill, the illness poses a disproportionate burden on health and social services. AN has inpatient costs alone that exceed that for schizophrenia. Chronic AN has the highest mortality rate of any mental illness. Chronic AN patients are known for their ambivalence about engaging in ....Anorexia nervosa (AN) is a serious mental illness that usually starts in adolescence and often runs a chronic course. With an estimated prevalence rate between 0.5% and 3.7% of women, and up to 50% remaining chronically ill, the illness poses a disproportionate burden on health and social services. AN has inpatient costs alone that exceed that for schizophrenia. Chronic AN has the highest mortality rate of any mental illness. Chronic AN patients are known for their ambivalence about engaging in treatment and poor motivation to change their eating disorder behaviours. They often fail to respond to traditional treatments and develop a history of negative treatment experiences and repeated treatment failures. A new approach is needed to reduce both the personal suffering and the burden of the illness on social and medical services. To date, there has been little scientific investigation into the development of specific treatment for those patients with chronic AN. This study will trial a recently manualised therapy - non-specific supportive clinical management - which initial evidence suggests may hold promise for chronic AN because it offers a more indirect, motivationally-matched approach. This treatment will be compared to the establishment therapy Cognitive Behavioural Therapy. Patients will be randomly allocated to one of the two treatment conditions and will receive 40 sessions over 12 months. They will be thoroughly assessed prior to during and after they have completed treatment and followed up for 6 months. This is the worlds first trial of a psychological treatment for chronic AN; it is hoped the study will establish an effective treatment for this debilitating and expensive illness. Further, as the project aims to explore the core, but often over-looked, feature of AN - poor motivation for recovery - it will also be in a position to shed light on the deep psychological processes that maintain this illness.Read moreRead less
Mechanisms Of Escape From Progesterone-induced Suppression: Role In Normal And Preterm Birth
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
Prematurity caused by preterm birth is the leading cause of death and disease among newborns in Australia. Here we will define how the length of pregnancy is determined by the opposing actions of progesterone, which maintains pregnancy, and prostaglandins, which induce labour. We will demonstrate the mechanism by which the actions of the two hormones are balanced in normal pregnancy and disrupted in preterm labour. We will show that preterm birth can be prevented by correcting the disorder.
A NOVEL MOUSE MODEL TO INVESTIGATE THE MECHANISMS OF VIRUS-INDUCED ARTHRITIS
Funder
National Health and Medical Research Council
Funding Amount
$336,000.00
Summary
We have developed a novel animal model by which to study arthritic disease caused by insect-transmitted viruses known as arboviruses. The existence of this model and novel reagents provides an excellent opportunity to further explore the basic mechanisms of infectious disease in a complete functioning animal, rather than specific cultured cells. The study will use modern approaches in molecular and cellular biology to achieve this goal. The production by our immune systems of soluble mediators ( ....We have developed a novel animal model by which to study arthritic disease caused by insect-transmitted viruses known as arboviruses. The existence of this model and novel reagents provides an excellent opportunity to further explore the basic mechanisms of infectious disease in a complete functioning animal, rather than specific cultured cells. The study will use modern approaches in molecular and cellular biology to achieve this goal. The production by our immune systems of soluble mediators (cytokines-chemokines) and antibodies is an overwhelming positive aspect of our physiological response to infection by microbes. Protection from disease by these immune compounds can happen naturally, or the body's ability to produce these factors can be exploited to our benefit via the administration of vaccines. However, these factors can also be detrimental to the host contributing to severe disease. For instance, work performed almost 40 years ago showed for the first time that under particular conditions, antibodies against viruses can enhance infection, instead of inhibiting infection as normally seen. In the intervening years work by scientists all over the world has associated antibody-dependent enhancement (ADE) of infection to many types of viruses; ADE is even thought to be a risk factor to serious disease with dengue virus, and has been shown in vitro for the AIDS virus and Ebola virus. We have recently discovered a molecular mechanism which explains how antibody enhances viral infection in vitro. In studies on immune cells infected with Ross River Virus (RRV) we found that infection helped by antibody resulted in the specific disruption to the production of cellular chemicals which are toxic to viruses. Are these mechanisms of antibody-enhanced infection also found in animals? Will such mode of infection cause enhanced disease and tissue pathology (arthritis) in animals?Read moreRead less
Estimating The Burden Of Group A Streptococcal Diseases In Victoria
Funder
National Health and Medical Research Council
Funding Amount
$386,760.00
Summary
Despite the considerable advances in the diagnosis and treatment of group A streptococcal (GAS) diseases made during the last century, the impressive spectrum of infections caused by this organism continues to have a significant impact in developed countries. This spectrum includes diseases that are mild but common (e.g. sore throat, skin sores), rare but very severe (e.g. bloodstream infections, flesh-eating bacteria) and those that are more common in developing countries and the Aboriginal pop ....Despite the considerable advances in the diagnosis and treatment of group A streptococcal (GAS) diseases made during the last century, the impressive spectrum of infections caused by this organism continues to have a significant impact in developed countries. This spectrum includes diseases that are mild but common (e.g. sore throat, skin sores), rare but very severe (e.g. bloodstream infections, flesh-eating bacteria) and those that are more common in developing countries and the Aboriginal population (e.g. rheumatic fever, kidney disease). Streptococcal sore throat remains one of the most common childhood infections, and severe group A streptococcal diseases are thought to be increasing in incidence in Australia. Yet, there are no accurate data on the incidence and costs of these or other GAS diseases in non-Aboriginal Australians, or in most other populations around the world. It is becoming more urgent to collect this data as numerous vaccine candidates are entering human trials, new approaches to the treatment of sore throat are emerging, and new strategies to treat and control the spread of severe disease are being developed. We propose a comprehensive strategy to measure the incidence, prevalence and costs of each group of GAS diseases. We will follow a group of families for 12 months to detect cases of GAS sore throat and skin sores and measure the impact on the family. We will survey children in schools to estimate the prevalence of skin sores. We will check hospital records to calculate the number of cases of rheumatic fever and kidney disease. And we will maintain surveillance for severe diseases by checking hospital and laboratory records. We will also check to see if family members of people with severe disease have the GAS bacterium in their throats. We will then compile these data into a comprehensive estimate of the burden of disease in Victoria, and estimate the cost-effectiveness of different treatment and prevention strategies.Read moreRead less
Molecular Studies Of The Astrocyte Reservoir Of HIV-1 In The Central Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$592,661.00
Summary
HIV infects the brain causing dementia in 10-20% patients. Strategies aimed at eradicating HIV infection fail to take into account CNS infection. Understanding the way in which HIV enters, infects and replicates in the brain is pivotal in development of drugs to prevent brain infection and dementia. Our studies have shown that HIV infection of the brain involves mechanisms distinct to those observed for blood and other organs. This study seeks to clarify such mechanisms.