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Role Of PLZF In Regulating The Interferon Response
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
The Interferon (IFN) pathway is essential for immune defense against pathogens in vertebrates. IFNs both protect and alert cells about viral, bacterial, and other immune assaults and promote a cellular antiviral state, reduce proliferation, or induce apoptosis depending on the cell type and environment. Based on these properties, IFNs have been used clinically against a variety of diseases including viral infections, immunomodulatory disorders and hematologic and solid tumors including renal cel ....The Interferon (IFN) pathway is essential for immune defense against pathogens in vertebrates. IFNs both protect and alert cells about viral, bacterial, and other immune assaults and promote a cellular antiviral state, reduce proliferation, or induce apoptosis depending on the cell type and environment. Based on these properties, IFNs have been used clinically against a variety of diseases including viral infections, immunomodulatory disorders and hematologic and solid tumors including renal cell carcinoma. However, the factors determining outcome of IFN treatment, remain to be determined. We have identified a subset of interferon stimulated genes whose sustained expression was found to correlate with heightened antiviral sensitivity of renal cell carcinoma cell lines to IFN. Many of these genes were found to have binding sites for the transcriptional repressor promyleocytic zinc finger protein (PLZF). PLZF was first identified in a subset of Acute Promyelocytic Leukemia patients and is involved in maintenance of erythroid lineage stem cells and spermatogonial stem cells in male mice. PLZF has not previously been implicated in the IFN response. Accordingly, we investigated the expression of interferon stimulated genes and showed that increased expression of immune related genes depends on PLZF expression. PLZF was also found to directly associate with binding sites in promoters of interferon stimulated genes and that this requires histone deacetylation. Thus, we uncovered a novel function for PLZF in enhancement of IFN associated gene expression. We propose to test the hypothesis that PLZF is an essential component of the IFN response. As a corollary, we will also test whether PLZF expression can be linked to IFN responsiveness in renal cell carcinoma. These studies will establish the role of PLZF in the IFN response and define its utility in predicting IFN responsiveness in therapeutic applications.Read moreRead less
The Importance Of GM-CSF In Determining The Fate And Function Of Dendritic Cell (DC) Subsets: Resident DC, Inflammatory DC And Suppressive DC.
Funder
National Health and Medical Research Council
Funding Amount
$334,053.00
Summary
The hormone GM-CSF determines how infections are seen by the immune system GM-CSF is a hormone already in use for increasing the production of white blood cells. We have found that it also affects their function, especially that of specialised white blood cells that process infectious materials to be recognised by the immune system. This project aims to detail the effects of GM-CSF on specialised white blood cells.
Role For Sphingosine Kinase-1 In Endothelial Progenitor Cell Survival And Differentiation.
Funder
National Health and Medical Research Council
Funding Amount
$294,205.00
Summary
Lay description: Collectively, diseases of the vascular system contribute immensely to the burden of health care in Australia. Notably, abnormal blood vessel formation and function (angiogenesis) has been identified as a major cause or contributor to the vascular complications associated with inflammation, cancer, rheumatoid arthritis and diabetes. Endothelial cells are one of the principle cells of blood vessels forming a barrier between the blood and tissues. This project aims to understand th ....Lay description: Collectively, diseases of the vascular system contribute immensely to the burden of health care in Australia. Notably, abnormal blood vessel formation and function (angiogenesis) has been identified as a major cause or contributor to the vascular complications associated with inflammation, cancer, rheumatoid arthritis and diabetes. Endothelial cells are one of the principle cells of blood vessels forming a barrier between the blood and tissues. This project aims to understand the process whereby mature endothelial cells are formed and how replacement of damaged endothelial cells is normally achieved. Stem cell therapy is considered the new frontier for the treatment of many diseases. Understanding how endothelial progenitor cells differentiate to mature endothelial cells and the signals which operate inside the cell may allow therapeutic manipulation of key target moecules in order to limit or control inflammation, tumourigenesis, rheumatoid arthritis and diabetic retinopathy. Our results suggest that one target maybe the enzyme sphingosine kinase.Read moreRead less
The human immune system comprises many different types of cells that can detect foreign molecules. My research will lead the way to understanding some of the most abundant, yet least well understood, cells within this system, collectively known as 'unconventional T cells'. This knowledge is essential to optimally and efficiently manipulate the immune system in health and disease.
TARGETING THE HUMAN CROSS-PRIMING DENDRITIC CELLS FOR IMMUNOTHERAPY
Funder
National Health and Medical Research Council
Funding Amount
$589,544.00
Summary
Specialized white blood cells called dendritic cells (DCs) are essential to inducing the immune system to eradicate cancers and viral infections in mice. We have defined human DC subsets and related their functional capacities to the mouse DC subsets. We will now identify the human DC subsets involved in the induction of cancer and viral immune responses and use this information to develop clinical therapeutic cancer vaccination trials.
Investigating The Mechanism And Consequences Of Cytotoxic Lymphocyte Detachment
Funder
National Health and Medical Research Council
Funding Amount
$419,180.00
Summary
Killer cells are white blood cells that destroy cancerous cells. To move to their next target they must quickly detach from a dying target. Failure of detachment results in excessive inflammation and tumour escape. This project will discover the detachment signals required to ‘release’ a locked-on killer cell. This will lead to a deeper understanding of immune pathology and new ways of treating cancer.
Asymmetric Cell Divison In T Cell Development: Consequences For Immunity And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$642,608.00
Summary
Human health depends upon the development of an immune system that can effectively control infection without damaging normal tissue. In this project, we assess a new paradigm by which immune cell development might be controlled, in which an immune cell precursor divides in such a way that its two daughters inherit different molecular constitutents that subsequently regulate the adoption of different cell fate. The likely consequences of this phenomonon on immunity and cancer will be explored.
My research centers on the formation and function of T cells, with particular emphasis on normal T cell homeostasis and how T cells respond to foreign antigens while tolerating self antigens.
Human Dendritic Cell Subsets And Their Application For Immunotherapy
Funder
National Health and Medical Research Council
Funding Amount
$443,946.00
Summary
Immunotherapy is a promising non-toxic strategy for the treatment of many cancers, viruses and other diseases. It works by teaching the patient's own immune system to recognize and destroy the cancer. Specialized blood cells called dendritic cells are essential to this process but they are poorly understood in humans. I aim to investigate the function these cells and use this information to develop new treatments for cancer and viruses.
The Adaptive Immune Response To Epstein-Barr Virus.
Funder
National Health and Medical Research Council
Funding Amount
$92,314.00
Summary
Epstein-Barr virus (EBV), the causative agent of glandular fever, is carried by a large proportion of adults worldwide. EBV is known to cause many cancers including Burkitt's lymphoma and has been linked to autoimmune diseases such as multiple sclerosis. The aim of this project is to find new fragments of EBV that the body's immune system can recognise and use to protect itself against the virus. Once found these pieces will form parts of the puzzle that will one day combine as a vaccine against ....Epstein-Barr virus (EBV), the causative agent of glandular fever, is carried by a large proportion of adults worldwide. EBV is known to cause many cancers including Burkitt's lymphoma and has been linked to autoimmune diseases such as multiple sclerosis. The aim of this project is to find new fragments of EBV that the body's immune system can recognise and use to protect itself against the virus. Once found these pieces will form parts of the puzzle that will one day combine as a vaccine against EBV.Read moreRead less