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Defining The Role Of GILZ In Inflammatory Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$675,030.00
Summary
Corticosteroids are commonly used to treat inflammatory diseases such as arthritis. Their action is based on effects on natural inflammation control pathways. One such pathway is that mediated by the protein known as GILZ (glucocorticoid induced leucine zipper). The function of this protein in disease is not well understood, and the research proposed here will increase understanding of its role. This knowledge could yield new treatments for arthritis and other inflammatory diseases.
Glucocorticoids (or 'steroids') are among the most commonly used drugs in the world, chiefly used for inflammatory diseases. However, they have major predictable side effects that have been known for over 60 years. Science has, til now, failed to deliver an alternative that delivers the effects of steroids without the side effects. This application is for funds to support the development of the discovery of the protein known as GILZ towards a treatment to help patients.
ADAMTS-5 Activity And The Effect Of A Dominant-negative Mutant
Funder
National Health and Medical Research Council
Funding Amount
$540,235.00
Summary
Cartilage loss is a feature of arthritis and is caused by enzymes. We discovered that loss of a critical cartilage component is caused by the enzyme ADAMTS-5. We also discovered that a mutant form of ADAMTS-5 blocks the normal emzyme, possibly by a novel binding interaction. If we can understand how this interaction works, we can exploit it for the design of new arthritis therapies. This project aims to identify the novel interaction and improve out understanding of cartilage destruction.
The Role Of SOCS-1 And SOCS-3 In Regulating Acute Inflammatory Arthritis.
Funder
National Health and Medical Research Council
Funding Amount
$444,910.00
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory disease which mainly targets joints. The disease causes chronic joint pain, stiffness and loss of joint mobility, leading to increasing difficulty in carrying out day to day activities. Treatment for RA has gradually improved, but remains inadequate for many patients. Although the cause is unknown, progress has been made in understanding the molecular pathways which drive RA. The disease is characterised by the production of high levels of infl ....Rheumatoid arthritis (RA) is a chronic inflammatory disease which mainly targets joints. The disease causes chronic joint pain, stiffness and loss of joint mobility, leading to increasing difficulty in carrying out day to day activities. Treatment for RA has gradually improved, but remains inadequate for many patients. Although the cause is unknown, progress has been made in understanding the molecular pathways which drive RA. The disease is characterised by the production of high levels of inflammatory mediators called cytokines. This finding has led to the development and introduction of specific cytokine inhibitors into clinical practice, although a significant number of patients fail to respond to treatment. An alternative approach to develop new treatments for RA would be to use the body's natural inhibitors to limit the actions of inflammatory cytokines. One such inhibitor is Suppressor of Cytokine Signalling-1 (SOCS-1). Using animal models, we have shown that mice lacking SOCS-1 develop more severe arthritis and have identified the different cell types it acts on. Further studies are still needed before SOCS-1 can be developed as a treatment for RA. We aim to identify the major cell type responsible for the increased severity of disease seen when SOCS-1 is absent. This will allow for treatment to be targetted to the most appropriate cells in the joint. We also aim to study the related molecule SOCS-3, to see whether it has similar effects on inhibiting the severity of disease. These studies will provide more information on the activity of SOCS proteins during inflammatory diseases in general and RA in particular and and may lead to new approaches for the treatment of RA.Read moreRead less
Monocyte Chemotactic Protein-1 (MCP1) And The PTH Anabolic Effect In Bone.
Funder
National Health and Medical Research Council
Funding Amount
$690,435.00
Summary
Chemokines and their receptors are major regulators of cell-cell interactions in many tissues. This project explores the strong increase of monocyte chemotactic protein-1 (MCP1 or CCL2) in bone, in a treatment where parathyroid hormone (a controller of calcium homeostasis) is used to increase bone mass to prevent osteoporosis. MCP1 was previously thought to be an inflammatory regulator, induced during infection and important in autoimmune conditions, so its role in bone was highly unexpected.
Inflammation-associated S100 Proteins: Links Between Arthritis And Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$454,691.00
Summary
Deeper understanding of the basic contributions of inflammation to cardiovascular disease can lead to better strategies for treatment and diagnosis. There are shared mechanisms in rheumatoid arthritis and these patients are at significantly higher risk of myocardial infarction and heart failure than the healthy normal population. This project will improve heart health because it will address how newly-recognised proteins, called S100 proteins, mediate pathogenesis and how they are regulated in c ....Deeper understanding of the basic contributions of inflammation to cardiovascular disease can lead to better strategies for treatment and diagnosis. There are shared mechanisms in rheumatoid arthritis and these patients are at significantly higher risk of myocardial infarction and heart failure than the healthy normal population. This project will improve heart health because it will address how newly-recognised proteins, called S100 proteins, mediate pathogenesis and how they are regulated in cells by various therapeutic drugs. We developed a potential diagnostic test that distinguishes patients with angina from those with arthritis and this could be useful in improving diagnosis and following treatment of patients with cardiovascular disease or arthritis. We find that some anti-inflammatory drugs enhance S100 gene expression whereas our preliminary data indicates that some cholesterol-lowering drugs (statins) reduce it. Results of treating patients with arthritis with statins will add to understanding of why cholesterol-lowering drugs commonly used in management of CVD patients may be effective in treating symptoms in arthritis sufferers and could contribute to changes in clinical management of these patients.Read moreRead less
Ankylosing spondylitis (AS) is a chronic arthritis which causes severe back and joint pain in young men and women. It can be difficult to diagnose as it takes years to show up on x-ray, and by then the joints are already damaged. This study looks at new ways to diagnose people with AS much earlier, which will allow earlier treatment and better outcomes. The study will also look at the role of lifestyle factors such as diet and physical activity which might impact on AS.
Can unloading footwear improve clinical care of people with knee osteoarthritis? Osteoarthritis is a public health problem imposing major economic and personal burden. It is the fourth highest cause of morbidity in Australia and national health expenditure in 2007 was $2.03 billion. Footwear can reduce knee load which is linked to disease pathogenesis. Specially-designed unloading shoes will be evaluated in a clinical trial and biomechanical studies to determine their efficacy at reducing sympto ....Can unloading footwear improve clinical care of people with knee osteoarthritis? Osteoarthritis is a public health problem imposing major economic and personal burden. It is the fourth highest cause of morbidity in Australia and national health expenditure in 2007 was $2.03 billion. Footwear can reduce knee load which is linked to disease pathogenesis. Specially-designed unloading shoes will be evaluated in a clinical trial and biomechanical studies to determine their efficacy at reducing symptoms, mechanical mechanism of pain relief, patient sub-groups that best respond to treatment and whether combined treatment with medial arch supports changes knee biomechanics. Outcomes will impact clinical practice and relieve suffering of people with knee osteoarthritis. Findings will also guide future shoe developments for arthritis. Read moreRead less