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Development And Biological Evaluation Of Cytokine Macrophage-migration Inhibitor (MIF) Non-Steroidal Antagonists
Funder
National Health and Medical Research Council
Funding Amount
$85,000.00
Summary
The cytokine macrophage-migration inhibitory factor (MIF) has a broad range of pro-inflammatory effects in the innate and adaptive immune system. CIA’s lab has demonstrated the potential importance of MIF in the pathology of chronic inflammation via studies in models of rheumatoid arthritis (RA). Similarly to other chronic inflammatory diseases, MIF is overexpressed in human RA, and induces activation of key pathological processes in RA cells. Moreover, antagonism of MIF with mAb profoundly inhi ....The cytokine macrophage-migration inhibitory factor (MIF) has a broad range of pro-inflammatory effects in the innate and adaptive immune system. CIA’s lab has demonstrated the potential importance of MIF in the pathology of chronic inflammation via studies in models of rheumatoid arthritis (RA). Similarly to other chronic inflammatory diseases, MIF is overexpressed in human RA, and induces activation of key pathological processes in RA cells. Moreover, antagonism of MIF with mAb profoundly inhibits models of RA and other inflammatory diseases, confirming MIF as a therapeutic target in human inflammatory disease. The X-ray crystal structure of MIF has been published and the putative active site fully characterised. We have deduced structural features of MIF that reveal aspects of the structural complementarity of host-guest affinity. This information has been used in the synthesis of new compounds to antagonise MIF. We have designed, synthesised and tested several classes of compounds, which have shown activity from milli to nano-molar levels in novel in-house in vitro bioassays.Read moreRead less
Evaluation Of Novel Pyrrolo/Iminoquinone Antimalarial Compounds
Funder
National Health and Medical Research Council
Funding Amount
$614,250.00
Summary
The development of new antimalarial drugs is an unmet global health priority. In this project we will investigate novel compounds that have been found to display promising in vitro antimalarial activity. We will modify these compounds to make them more drug-like, and assess their efficacy in vivo using malaria animal models. These studies have the potential to identify compounds that may result in a new therapy for malaria, the worlds' most significant tropical infectious disease.
The Design And Synthesis Of Sialyltransferase Inhibitors As Anti-metastatic Agents
Funder
National Health and Medical Research Council
Funding Amount
$273,629.00
Summary
The prevalence of cancer and, in particular, cancer that spreads throughout the body has risen over the past twenty years in the human population and causes significant human mortality. A correlation between some of a cancerous cell's surface componentary and the ability of this cell to spread throughout the body has been established. This research project will provide a range of chemical entities (probes) that will intervene in this spreading process (metastasis). These probes will be the basis ....The prevalence of cancer and, in particular, cancer that spreads throughout the body has risen over the past twenty years in the human population and causes significant human mortality. A correlation between some of a cancerous cell's surface componentary and the ability of this cell to spread throughout the body has been established. This research project will provide a range of chemical entities (probes) that will intervene in this spreading process (metastasis). These probes will be the basis for a drug discovery programme that targets a particular aspect of the spreading process. Through molecular modelling, drug candidate synthesis and evaluation of these compounds in relevant test tube (in vitro) assays it is envisaged that a number of candidate compounds will then be evaluated in an animal model (in vivo assay). The technology to be used in this project is comparable to that which we used in the discovery of the recently approved influenza drug, Relenza?.Read moreRead less
Antagonist Of Corticotrophin Releasing Hormone As Therapeutic Agents For The Prevention Of Premature Birth In Humans
Funder
National Health and Medical Research Council
Funding Amount
$376,650.00
Summary
In developed countries the most common cause of the death of a newborn baby is premature delivery. Pre-term delivery remains the greatest cause of neonatal mortality in the western world and a major consumer of health dollars (approx. $5-7B per year in the US alone). However, a delay in the onset of labour from 20 to 25 weeks has been shown to result in a 55% greater probability of infant survival (550 fewer deaths per 1000). This project will allow: The development of new drugs that will allow ....In developed countries the most common cause of the death of a newborn baby is premature delivery. Pre-term delivery remains the greatest cause of neonatal mortality in the western world and a major consumer of health dollars (approx. $5-7B per year in the US alone). However, a delay in the onset of labour from 20 to 25 weeks has been shown to result in a 55% greater probability of infant survival (550 fewer deaths per 1000). This project will allow: The development of new drugs that will allow the extension of pregnancy term The development of protocols that will in turn reduce neonatal mortality. Additionally we believe that these new agents will be useful in preventing the onset of labour after fetal surgery. Currently there are no effective treatments capable of substantially changing delivery dates. Available therapeutics delay the onset of labour, at best, 24 hours. However, recent exciting results from our laboratories show that rising concentrations of the placental peptide Corticotrophin Releasing Hormone (CRH) are associated with the onset of labour. Further, we have also delayed the onset of labour in pregnant sheep by infusing a relatively insoluble CRH antagonist into the sheep fetus. Labour commenced ONLY AFTER the drug was withdrawn from the mother. This project builds upon an interdisciplinary team: medicinal chemists, molecular modellers, pharmacologists and endocrinologists, to further develop an exciting Australian discovery. Successful completeion of this research will, for the first time, allow the control of pregnancy duration MAXIMISING the benefits to mother and child, reducing mortality and later life morbidities typically associated with premature birth.Read moreRead less
Studies Of Metabolites Of Synthetic Flavonols For The Treatment Of Cardiovascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$207,440.00
Summary
Cardiovascular disease, including heart attack and stroke, is the leading killer of Australians. A promising new drug, NP202, can reduce the amount of tissue damaged from a heart attack; however, its mechanism of action remains obscure. NP202 is metabolized to a range of compounds, one of which is partly responsible for its beneficial effects. In this project we will identify other metabolites of NP202 and characterize their biological activity to gain insight into its mechanism of action.
Preclinical Evaluation Of F-18 Fluoroethyltriazolyl PEGstilbenes As Potential PET Imaging Agents For Alzheimers Disease
Funder
National Health and Medical Research Council
Funding Amount
$673,238.00
Summary
Alzheimer's disease (AD) is the most common form of dementia and is becoming am ever increasing burden to the health system due to the aging of our population. Amyloid plaques are considered the hallmark of AD and a technique for their detection in vivo would be a breakthrough, not only for the diagnosis of AD but also for the development of drugs against AD. Nuclear medicine can image tissue function non-invasively. This project aims to develop new imaging agents to improve diagnosis of AD.
Developing Inhibitors Of An Essential Histidine Kinase In Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$578,352.00
Summary
Staphylococcus aureus (Golden staph) has been termed a "superbug" because of its persistent ability to acquire resistance to a wide range of antibiotics. Once considered primarily a hospital-acquired pathogen, many patients are now being infected with antibiotic-resistant Golden staph outside of hospitals. The primary aim of this research program is to develop new antibiotics to treat antibiotic-resistant strains of Staphylococcus aureus and related pathogens.
Exposure And Risks From Persistent Organic Pollutants Through Consumption Of Traditional Seafood
Funder
National Health and Medical Research Council
Funding Amount
$322,042.00
Summary
For many coastal Aboriginal and Torres Strait Islander people, local marine resources provide an important and integral aspect of the communities' diet, culture and traditions. The health benefits associated with seafood consumption have been well documented. On the other hand, many environmental contaminants accumulate in the marine environment. In particular persistent organic pollutants (POPs) have the potential to accumulate to elevated levels in the marine food chain, including humans. Cons ....For many coastal Aboriginal and Torres Strait Islander people, local marine resources provide an important and integral aspect of the communities' diet, culture and traditions. The health benefits associated with seafood consumption have been well documented. On the other hand, many environmental contaminants accumulate in the marine environment. In particular persistent organic pollutants (POPs) have the potential to accumulate to elevated levels in the marine food chain, including humans. Consumption of food contaminated with POPs can pose a risk of causing adverse health effects, including cancer, endocrine disruption, developmental and immunotoxic responses. Recent studies in Queensland have shown elevated concentrations of POPs, specifically dioxins, in the near shore marine environment. Concentrations present in dugong and turtle tissues were found to be among the highest reported compared to other marine biota worldwide. These species represent an integral part of the traditions and diet for many coastal Aboriginal and Torres Strait Islander communities. However, to date no information on exposure to these compounds from locally sourced seafood exists in Australia. The proposed study will redress this lack of information and provide an understanding of the risks associated with the consumption of traditional seafood from local contaminated areas. In collaboration with the Quandamooka community, Moreton Bay in South East Queensland this will provide a case study with the objectives of: 1. Assessing the qualitative and quantitative risks associated with consumption of traditional and contemporary seafood sourced from local contaminated areas. 2. Providing communities with a thorough understanding of food contamination and building internationally competitive capacity in Australian Indigenous researchers. 3. Develop risk management options that allow informed decisions making on POP exposure and are acceptable to the community.Read moreRead less