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RNA Interference In Model Systems Of Macular Degeneration.
Funder
National Health and Medical Research Council
Funding Amount
$166,500.00
Summary
Exudative age-related macular degeneration (AMD) is the most common cause of irreversible severe vision loss in the elderly, with an estimated 25-30 million people worldwide blind due to AMD. There is currently no standard treatment for AMD. A safe, specific and effective pharmacologic agent for AMD, therefore, has enormous therapeutic, social and economic benefits. AMD is underpinned by vascular leakiness and new blood vessel formation. We have demonstrated that Egr-1, a nuclear transcription f ....Exudative age-related macular degeneration (AMD) is the most common cause of irreversible severe vision loss in the elderly, with an estimated 25-30 million people worldwide blind due to AMD. There is currently no standard treatment for AMD. A safe, specific and effective pharmacologic agent for AMD, therefore, has enormous therapeutic, social and economic benefits. AMD is underpinned by vascular leakiness and new blood vessel formation. We have demonstrated that Egr-1, a nuclear transcription factor, plays a key regulatory role in a diverse array of angiogenic processes. In this project, we will use novel gene-targeting agents (Egr-1 siRNA) to provide preclinical proof-of principle evidence of their therapeutic potential in established animal models of AMD. These studies will pre-empt Phase IA safety trials in AMD patients.Read moreRead less
Developing Anti-Inflammatory Drugs Based On Inhibition Of A Human Enzyme
Funder
National Health and Medical Research Council
Funding Amount
$160,000.00
Summary
Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading membrane phospholipids to inflammatory mediators like arachid ....Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading membrane phospholipids to inflammatory mediators like arachidonate, PAF, prostaglandins, leukotrienes, etc. there is a consensus that blockade of phospholipid metabolism would represent a major advance on NSAIDs as antiinflammatory agents. No sPLA2-IIa inhibitor is available yet in man. We aim to create an attractive data package showing proof of concept for a potent new type of antiinflammatory drug. This data will give us an improved negotiating position in our commercialisation of a new drug with potential multi-billion dollar markets as diverse as arthritis, asthma, reperfusion injury, organ transplantation and many other currently intractable human ailmentsRead moreRead less
Development Of Anti-CXCR2 Monoclonal Antibodies For Tumour Therapy
Funder
National Health and Medical Research Council
Funding Amount
$174,867.00
Summary
New therapies to treat cancers and inflammatory diseases are urgently required. Our aim is to develop a new treatment for cancer and inflammation, by blocking the chemokine receptor CXCR2 which is central to angiogenesis (blood vessel growth) and inflammation. We have produced a highly effective monoclonal antibody (mAb) inhibitor of CXCR2, that is suitable for preclinical and clinical development. The project aims to examine the efficacy of this mAb in mouse tumour models and inflammation.
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
Development Of A Highly Potent, Fully Human Anti-GM-CSF Monoclonal Antibody
Funder
National Health and Medical Research Council
Funding Amount
$334,000.00
Summary
Many diseases, such as arthritis, have unwanted inflammatory reactions. Better drugs are needed to control inflammation. A powerful antibody to a significant pro-inflammatory cytokine will be generated; this antibody will be especially designed so that it will not be rejected by patients. Because of its properties it will cost the community less than similar therapeutics. Because inflammatory diseases are common many patients will benefit from our therapeutic.
Development Of An Anti-GM-CSF Antibody For Treatment Of Rheumatoid Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$283,000.00
Summary
The aim of this project is to develop assays for the evaluation of the efficacy and safety of an anti-GMCSF neutralizing antibody in a Australian first-in-man clinical trial in patients with severe rheumatoid arthritis (RA). This chimeric antibody has been developed by the Ludwig Institute for Cancer Research, Melbourne Branch, in conjunction with KaloBios Pharmaceuticals, Inc., USA. It is intended to use the assays developed in this project to facilitate commercial development of this antibody, ....The aim of this project is to develop assays for the evaluation of the efficacy and safety of an anti-GMCSF neutralizing antibody in a Australian first-in-man clinical trial in patients with severe rheumatoid arthritis (RA). This chimeric antibody has been developed by the Ludwig Institute for Cancer Research, Melbourne Branch, in conjunction with KaloBios Pharmaceuticals, Inc., USA. It is intended to use the assays developed in this project to facilitate commercial development of this antibody, and result in the development of an improved treatment for this devastating disease.Read moreRead less
Development And Evaluation Of Novel Anti-inflammatory Products Derived From An Indigenous Medicinal Plant
Funder
National Health and Medical Research Council
Funding Amount
$276,598.00
Summary
This collaborative project between researchers at the University of South Australia and Indigenous traditional owners from Northern Kaanju homelands (Cape York Peninsula, Qld) will develop and evaluate products derived from the Northern Kaanju medicinal plant Dodonaea polyandra. Extracts of the plant and novel compounds isolated from it have anti-inflammatory activity. These have the potential to be used in inflammatory diseases such as dermatitis, arthritis and inflammatory bowel disease.
Development Of A Simple Chemical Test For Detecting DNA-interacting Compounds For Medical And
Funder
National Health and Medical Research Council
Funding Amount
$315,450.00
Summary
The project exploits a simple chemical reaction to detect and measure the interaction of compounds with DNA. The test will be useful in the early screening of drug candidates for genotoxicity, identifying new anticancer drugs and also find application in the environmental, cosmetic and food industries. Work will focus on establishing peak conditions for the test, determining the scope of application, testing a panel of control compounds and performing a blind study to provide proof of concept.
Development Of Anti-metastatic And Tumour Targeting Reagents By Design Of Inhibitors To Specific Eph/ephrin Cell-cell
Funder
National Health and Medical Research Council
Funding Amount
$200,000.00
Summary
Metastatic disease, malignant melanoma in particular, is a health issue of considerable global importance with 1,000 fatal melanoma cases- year in Australia alone. While progress has been made on prevention and early diagnosis, no curative treatment exists for stage IV melanoma. Tumour progression and the acquisition of metastatic competence primarily reflect dysregulation of cell adhesion and cell motility rather than proliferation and survival. In this context, Eph receptor tyrosine kinases (E ....Metastatic disease, malignant melanoma in particular, is a health issue of considerable global importance with 1,000 fatal melanoma cases- year in Australia alone. While progress has been made on prevention and early diagnosis, no curative treatment exists for stage IV melanoma. Tumour progression and the acquisition of metastatic competence primarily reflect dysregulation of cell adhesion and cell motility rather than proliferation and survival. In this context, Eph receptor tyrosine kinases (Ephs) and their membrane-bound ephrin ligands are crucial mediators of cell adhesion and motility and are notably overexpressed in metastatic tumours rather than primary (benign) lesions5. Our laboratories were the first to identify EphA3 7, and one of the first to isolate its ligand, ephrin-A5. EphA3 was isolated from acute lymphoblastoid leukemia and malignant melanoma patients, where increasing expression levels correlate with metastatic progression. Soluble, non-clustered forms of Ephs and ephrins are effective inhibitors of Eph activity 3 and provide opportunities to generate specific drugs for cancer therapy. We now propose a research and development program for the development of EphA3-specific drugs and their production for pre-clinical and clinical evaluation for placement onto a national and international market.Read moreRead less
Stage II In The Development Of Eph/ephrin Based Tumor Targeting Reagents: Optimisation Of Drug Efficacy And Delivery
Funder
National Health and Medical Research Council
Funding Amount
$204,125.00
Summary
In the final stage of cancer, including melanoma, tumor cells gain the ability to spread, a process called metastasis. Altered communication between cancer and normal cells is one of the causes of this invasive characteristic. We have started the development of novel agents that target and modulate proteins on the cell surface that control these properties and are found in metastatic tumors. We propose to refine the targeting and killing properties of these agents for early clinical testing.