Cancer arises through a combination of common DNA mutations which are associated with very poor survival in certain cancers. However, the cause of these mutations was always believed to be external factors (eg. UV light, toxins), Our exciting preliminary results show internal molecules, called circular RNAs, can drive these mutations and this project will investigate how this occurs and study whether targeting these molecules can reduce the incidence of cancers.
Targeting The Oncoprotein MDMX As A Novel Treatment For Triple Negative Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$561,672.00
Summary
Breast cancer (BrCa) is a leading cause of cancer death in women worldwide. BrCas unable to respond to current therapies have the worst outcomes. We propose a novel strategy to treat these cancers, based on our new findings. Our two protein targets are: (1) MDMX, that we found drives BrCa with its partner, (2) mutant p53, which causes cancer spread. We plan to directly target these drivers of aggressive BrCas, using new drugs that individually show great promise in trials in a number of cance
Deciphering The Role Of DNA Methylation In The Regulation Of Alternative Splicing
Funder
National Health and Medical Research Council
Funding Amount
$865,494.00
Summary
When a gene is turned on, the messenger RNA must be correctly processed to generate functional proteins. This ‘splicing’ process is essential for normal cellular activity, and is disrupted in many human diseases. We have discovered that an epigenetic modification, DNA methylation (mC), may control splicing. This project will investigate how mC influences splicing and use new epigenome-editing tools to control it, in order to ultimately understand and treat diseases involving aberrant splicing.
Investigating The Role Of Aberrant Splicing (intron Retention) In Acute Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$1,135,745.00
Summary
In 2013, we made a breakthrough discovery that certain parts of genes, previously considered “Junk DNA”, are actually carrying signals to control the amount of proteins produced in cells. Our preliminary work now suggests these signals controlling protein levels can be faulty in cancers. Here, we wish to determine whether these faulty signals could cause a deadly blood cancer called acute myeloid leukaemia (AML). We aim to decipher previously unknown causes of AML that will spur novel therapies.
Deciphering The Role Of Intron Retention In Monocyte Differentiation And Function
Funder
National Health and Medical Research Council
Funding Amount
$511,114.00
Summary
In 2013, we made a breakthrough discovery that certain parts of genes, previously considered “Junk DNA”, are actually carrying signals to control the amount of proteins produced in cells. We now wish to understand the roles of these signals in the development of a key immune cell called monocyte. Monocytes are important to fight infection and inflammation in diseases such as diabetes and cancer. We hope to advance our knowledge on how we can manipulate these cells for therapeutic gain.
Role Of The MiR-200 Target Quaking In Alternative Splicing During EMT And Cancer Progression
Funder
National Health and Medical Research Council
Funding Amount
$443,160.00
Summary
The spread of cancer to other organs involves cancer cells changing to a more aggressive state and is a major cause of cancer related death. MicroRNAs are a class of genes that control whether cancer cells become more aggressive by regulating other genes. In this project we will examine the function of a new microRNA target which controls the cancer cell aggression. The outcome will be a better understanding of how cancers spread and the identification of new therapeutic targets.
Characterising Novel Alternative Splicing Networks That Promote Tumour Cell Plasticity
Funder
National Health and Medical Research Council
Funding Amount
$609,329.00
Summary
During cancer progression, tumour cells can change their properties and become more aggressive and resistant to therapies. We have identified an important regulator of this tumour cell transition, called “Quaking”, which causes widespread changes in gene splicing. We aim to investigate how "Quaking" causes changes in gene splicing and what the effects of these splicing changes are in tumour cells.
Alternative Splicing- A Regulatory Mechanism Determining Self-renewal And Pluripotency Of ES And IPS Cells
Funder
National Health and Medical Research Council
Funding Amount
$664,650.00
Summary
Stem cells hold great promise in cell replacement therapies and may provide models to study human diseases and to screen new pharmaceuticals. For successful future therapeutic applications, a deeper understanding of the molecular mechanisms governing the behavior of stem cells is crucial. In this proposal we will investigate the role of alternative splicing in the control of the fundamental properties of stem cells, and identify target RNAs and gene expression networks regulated by splicing fact ....Stem cells hold great promise in cell replacement therapies and may provide models to study human diseases and to screen new pharmaceuticals. For successful future therapeutic applications, a deeper understanding of the molecular mechanisms governing the behavior of stem cells is crucial. In this proposal we will investigate the role of alternative splicing in the control of the fundamental properties of stem cells, and identify target RNAs and gene expression networks regulated by splicing factors.Read moreRead less
Intron Retention Regulation In Granulopoiesis And Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$574,419.00
Summary
Our project will shed light on the development of white blood cells, and what goes wrong when they become cancerous. In particular we have uncovered an unexpected control mechanism of gene expression in these cells. This mechanism governs the specific removal of molecules involved in transmitting information in cells (mRNAs). By extending our research to a cancer of white blood cells called chronic myeloid leukaemia, we hope to provide new insights into its causes and discover targets for innova ....Our project will shed light on the development of white blood cells, and what goes wrong when they become cancerous. In particular we have uncovered an unexpected control mechanism of gene expression in these cells. This mechanism governs the specific removal of molecules involved in transmitting information in cells (mRNAs). By extending our research to a cancer of white blood cells called chronic myeloid leukaemia, we hope to provide new insights into its causes and discover targets for innovative drugs.Read moreRead less
Uncovering New Epigenetic-based Regulatory Mechanisms Of Gene Expression: Novel Links Between Histone Variants, RNA Function And Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,053,671.00
Summary
It is estimated that greater than 90% of human genes undergo alternative RNA splicing, which can explain how protein diversity is achieved with a limited number of genes. However, how alternative splicing patterns are established remains poorly understood but is an important question given that 15-50% of human disease mutations are associated with changes to the splicing patterns of RNA. We have uncovered a new splicing mechanism, which involves changing the way DNA is packaged in a cell.