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.
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.
The Role Of The Neuronal Splicing Factor A2BP1 In Autism Spectrum Disorders
Funder
National Health and Medical Research Council
Funding Amount
$396,412.00
Summary
Autism spectrum disorders (ASD) are characterized by language deficits, social impairments and repetitive-restrictive behaviors. ASD is one of the most highly heritable neuropsychiatric conditions, and at the same time genetically very heterogeneous. We have recently shown that shared gene expression abnormalities can be identified in postmortem brain from ASD patients. We now propose to investigate the mechanisms and functional consequences of gene expression abnormalities in ASD.
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.
Splice Correction As A Treatment For Rare Diseases
Funder
National Health and Medical Research Council
Funding Amount
$824,316.00
Summary
We propose that a strategy of bringing effective and personalised treatments to amenable patients with rare genetic diseases, though ambitious, is readily achievable and opportune. Importantly, a consensus approach will facilitate expediting potentially curative treatments for many patients with rare diseases that would be unlikely to be commercially viable if considered individually.
Targeted Alternative Splicing: A Common Therapeutic Platform To Treat Inherited Diseases
Funder
National Health and Medical Research Council
Funding Amount
$797,165.00
Summary
Genes consist of exons (protein coding domains) separated by introns (non-coding intervening sequences). It is now evident that not every exon need be included in the gene message to direct synthesis of a functional gene product. This application seeks to identify which exons are essential for gene function and those exons that are "dispensable". Such information will allow personalized therapies to be developed based on splice switching, as we have done for Duchenne muscular dystrophy.
Novel Early Detection Strategy For Liver Cancer Using Hepatitis B Splice Variants To Expediate Diagnosis And Improve Treatment Outcome
Funder
National Health and Medical Research Council
Funding Amount
$943,566.00
Summary
Hepatitis B virus (HBV) causes liver cancer, which is one of the only cancers that is increasing in prevalence. We have shown that smaller versions of HBV, termed splice variants, are even more strongly associated with liver cancer- people with higher levels of the splice variants were over 3 times more likely to have liver cancer. We will find out why, by thoroughly studying how the splice variants alter the virus and the host cell to promote liver cancer.