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A New Model Of T Cell Lymphoma Induced By An Ets Transcription Factor
Funder
National Health and Medical Research Council
Funding Amount
$679,091.00
Summary
The identification of leukaemia-causing genes is crucial as once these are found new specific drugs can be developed. This is best exemplified by the new drug, Gleevec, that inhibits a leukaemia-causing gene in myeloid leukaemia. This has allowed a large reduction of high chemotherapy treatment but has induced remission in around 80% of patients. This proposal has identified a novel leukaemia-causing gene for T cell leukaemia. Therefore, new specific drugs can now be made to inhibit it.
The proposed program of work aims to shed light on dietary, environmental and genetic factors that may be related to the risk of childhood cancers. Identifying these risk factors, and how they interact with each other, will provide clues as to how childhood cancers may be prevented. The research program includes a number of Australian and international studies, which will involve collaboration between doctors and research scientists from a range of disciplines.
Analysis Of The Interaction Of The T-cell Oncoproteins Scl And Lmo2 In T Cell Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$179,149.00
Summary
Leukaemic cells frequently contain alterations to the chromosomes which contribute to the generation of the leukaemia by causing the expression of cancer-promoting genes. In the case of T cell acute lymphoblastic leukaemia (T-ALL), the most frequent target of chromosomal alterations is the Stem Cell Leukaemia gene, or SCL. In leukaemic cells, the SCL protein is found to be associated with another protein, called Lmo2, the gene for which is also activated due to chromosomal alterations in T-ALL. ....Leukaemic cells frequently contain alterations to the chromosomes which contribute to the generation of the leukaemia by causing the expression of cancer-promoting genes. In the case of T cell acute lymphoblastic leukaemia (T-ALL), the most frequent target of chromosomal alterations is the Stem Cell Leukaemia gene, or SCL. In leukaemic cells, the SCL protein is found to be associated with another protein, called Lmo2, the gene for which is also activated due to chromosomal alterations in T-ALL. It is thought that these two proteins must bind each other to cause leukaemia, but this has never been proven. This project aims to test whether removal of SCL and Lmo2 is able to stop the progress of leukaemias which they initiate. We will do this by overexpressing SCL and Lmo2 to establish leukaemia in mice, then removing these genes to see if the leukaemia is cured. We will then test whether removal of the endogenous SCL protein is able to stop the onset and progress of leukaemias initiated by Lmo2. We will do this by removing SCL in mice which overexpress Lmo2. Lastly we will generate mutant SCL proteins which are unable to interact with Lmo2, and co-express these along with Lmo2 in mice to assess whether they are able to co-operate with Lmo2 in causing leukaemia. We predict these mutants which are unable to bind to Lmo2 will be unable to co-operate with it in causing leukaemia. This will identify regions of these proteins which can be used as targets for anti-leukaemia drug development.Read moreRead less
Genome-wide Epigenetic Analysis Of Childhood Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$410,469.00
Summary
Of all cancers in children, Acute Lymphoblastic Leukaemia is the most common. To date, the causal mechanism(s) for leukaemia in children remain unclear. Although 5-year event-free survival rates are relatively high (up to 80%) it is still unclear why children expected to survive with a good prognosis, succumb to the disease. Therefore, there is still a need to further refine current diagnosis and prognosis parameters that will together lead to improved outcomes to children with leukaemia.
The Role Of Thymocyte Self-renewal In Causing T Cell Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$586,594.00
Summary
Recurrence of acute leukamia after therapy is due to the presence of immature cells that can self-renew, a process that is normally restricted to stem cells. Through the study of mice that develop leukaemia, we have identified these very rare self-renewing cells that are resistant to standard therapies. We can identify and measure these cells many months before leukaemia develops. As such, we will use this mouse model to understand how these cells self-renew and how they can be killed
Antagonists Of P38 MAPK As Therapeutics For Acute Lymphoblastic Leukemia.
Funder
National Health and Medical Research Council
Funding Amount
$521,961.00
Summary
New therapies are needed to treat patients with leukemia. Moving leukemic cells into the blood reduces their growth and increases the effects of chemotherapy. Currently we cannot move leukemic cells into the blood without moving normal blood forming cells, making them more sensitive to chemotherapy. We have identified a drug that only affects leukemic cell movement. This study will examine the potential of this drug to treat leukemia.
Development And Assessment Of Novel Assays To Predict Response To Second-line TKI Therapy In Imatinib-resistant CML
Funder
National Health and Medical Research Council
Funding Amount
$491,308.00
Summary
Patients with chronic myeloid leukaemia (CML) respond well to imatinib, the first small molecule developed to block the kinase activity of the causative oncogene in CML, BCR-ABL. However some patients develop resistance. Several new kinase inhibitors are now available that are effective in some patients with imatinib resistance. We plan to develop biological and molecular assays to predict if a CML patient will respond to a specific second-line kinase inhibitor to optimise second-line therapy.
Childhood Precursors Of Adult Cardiovascular Disease, Obesity And Diabetes- 16 Year Follow Up Of A Longitudinal Cohort
Funder
National Health and Medical Research Council
Funding Amount
$835,631.00
Summary
There is a world wide 'epidemic' of obesity and diabetes with rates tripling in young adults in the last twenty years. This is likely to lead to an upsurge in heart attack and stroke and to reverse many of the gains seen in this area in Australia. This project aims to study the childhood and antenatal precursors for the risk of adult obesity, diabetes, heart disease and stroke. The study involves The Perth longitudinal childrens 'Raine' cohort, a unique group of just under 3000 children, first m ....There is a world wide 'epidemic' of obesity and diabetes with rates tripling in young adults in the last twenty years. This is likely to lead to an upsurge in heart attack and stroke and to reverse many of the gains seen in this area in Australia. This project aims to study the childhood and antenatal precursors for the risk of adult obesity, diabetes, heart disease and stroke. The study involves The Perth longitudinal childrens 'Raine' cohort, a unique group of just under 3000 children, first monitored in the womb before mid pregnancy and then repeatedly through to the age of 13 years. Every 2 to 3 years the study children have been carefully assessed for changes in fatness, blood pressure and more recently, nutrition, physical activity and fitness, blood cholesterol and tendency to diabetes. Families have also been carefully monitored for a range of social characteristics and mental health. We already have evidence that about a fifth of the children at age 8 are particularly at risk of obesity, diabetes and cholesterol problems and high blood pressure. We now plan to study the children after puberty at age 16, when they will be adopting a range of more adult behaviours which may profoundly affect these risks. This study will provide comprehensive information on the children from before birth to adolescence and help pinpoint ways in which growth in the womb, and subsequent childhood behaviour interacts with influences of family, social factors, environment and mental health to affect long term risk of obesity, premature diabetes or heart disease. The study will also provide a basis for future examination of the links between genes, environment and health.Read moreRead less
Obesity, Self Image, Eating Behaviour, Nutriton And Activity In Australian Preadolescent School Children.
Funder
National Health and Medical Research Council
Funding Amount
$167,328.00
Summary
Obesity in children is increasing, but there is a great deal of concern about whether education about diet and obesity will produce eating disorders. While there is a lot of information about the eating practices, body image worries and self esteem in teenagers, there is no information really available about what primary school children in this country know about eating, about whether they diet or not, where they get their information about dieting and about their self esteem and body image part ....Obesity in children is increasing, but there is a great deal of concern about whether education about diet and obesity will produce eating disorders. While there is a lot of information about the eating practices, body image worries and self esteem in teenagers, there is no information really available about what primary school children in this country know about eating, about whether they diet or not, where they get their information about dieting and about their self esteem and body image particularly if they are overweight or very thin. It is important to gather this information as it is in the teen years that problems about eating and body image really emerge. These concerns must be starting in primary school children, This study aims to gather this information and more from 2442 primary school children across NSW. This information will enable proper education programs about eating, body image and obesity to be developed so no harm is caused by trying to reduce obesity. This study will also gather important information about how many children are obese or have eating disorders and will see what part their physical activity plays in their weight and the way they go about controlling it. To have healthy adults in the next generation, with less obesity and eating problems, it is important to gather information about nutrition and eating beliefs, dieting, body image and self esteem in children now.Read moreRead less
Novel Artemisinin-based Combination Therapies For Children Exposed To High Transmission Of Multiple Plasmodium Species
Funder
National Health and Medical Research Council
Funding Amount
$1,378,408.00
Summary
We recently found that the WHO-recommended combination antimalarial therapy artemether-lumefantrine and the candidate regimen dihydroartemisinin-piperaquine were not fully effective for both falciparum and vivax malaria in young PNG children, a group at risk of complications and death. We plan to study two new combinations (artesunate-pyronaridine and artemisinin-naphthoquine) and hypothesise that at least one will prove superior and be used as first-line treatment in PNG and similar countries.