I am a molecular biologist determining the mechanisms of eukaryotic mRNA translation and its regulation by RNA-binding proteins and noncoding RNA. In collaborative work I extend these basic science objectives into the medical research areas of cardiology
The Role Of Food Components In The Modification Of Colorectal Cancer Risk At The Epigenomic Level.
Funder
National Health and Medical Research Council
Funding Amount
$28,609.00
Summary
Colorectal cancer represents a substantial burden to the health system. Primary prevention rather than treatment is more cost effective and can reduce morbidity and mortality. This study program will contribute to the emerging research area of nutrigenomics and nutritional epigenomics, by investigating the interaction between nutrition and gene expression. Such research can assist in establishing a diet which can best help to prevent colorectal cancer, at an individual or population level.
Functional Characterization Of The Regulatory Architecture Of Melanoma-associated Loci
Funder
National Health and Medical Research Council
Funding Amount
$645,663.00
Summary
Melanoma accounts for more than 75% of skin cancer related deaths. In Australia, >10,000 new cases are diagnosed yearly. In this proposal, we will apply novel genetic sequencing technologies developed in our laboratory to examine genomic regions that are associated with melanoma development. By focusing on selected areas, we will obtain a much deeper understanding of how these genes are regulated and find new ways of detecting and treating this disease.
Investigation Into The Alternative Splicing Of Steroid Hormone Regulated Genes In Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
Steroid hormones have imortant roles in breast tissue growth and differentiation. We have identified several proteins called PRMT6 and CAPER's , that are involved in steroid hormone signaling and control the alternative splicing of RNA, the process in which several different proteins can be produced from a single gene. Our aim is to study these proteins in an effort to understand how they influence alternative splicing and to identify genes they control in relation to breast cancer.
C-JUN TARGETING STRATEGIES AS NOVEL CARDIOPROTECTIVE AGENTS IN ISCHAEMIA-REPERFUSION INJURY
Funder
National Health and Medical Research Council
Funding Amount
$361,148.00
Summary
Acute myocardial infarction (AMI) and its sequelae are an increasing problem in terms of morbidity, mortality and healthcare costs in Australia and the industrialised world; in the USA this is estimated annually at 900,000 and 225,000 patients and US$60 billion, respectively. Current treatment for AMI includes mechanical (percutaneous coronary intervention) or thrombolytic therapy; however, these approaches are directed primarily at epicardial arteries rather than the myocardium and are, therefo ....Acute myocardial infarction (AMI) and its sequelae are an increasing problem in terms of morbidity, mortality and healthcare costs in Australia and the industrialised world; in the USA this is estimated annually at 900,000 and 225,000 patients and US$60 billion, respectively. Current treatment for AMI includes mechanical (percutaneous coronary intervention) or thrombolytic therapy; however, these approaches are directed primarily at epicardial arteries rather than the myocardium and are, therefore, suboptimal. Strategies aimed at directly protecting cardiomyocytes from ischaemia-reperfusion injury, reducing leukocyte recruitment and myocardial cell death, would complement current approaches restoring epicardial artery flow and are keenly sought. This project will demonstrate the capacity of two separate gene-silencing strategies (DNAzymes and siRNA to suppress the expression of the immediate-early gene, c-Jun in cardiomyocytes and reduce infarct size, left ventricular dysfunction, apoptosis, inflammation, production of reactive oxygen species, angiogenesis and fibrosis in the injured rat myocardium. It will also shed light on the molecular mechanisms underlying c-Jun-mediated myocardial inflammation. As such, these studies will provide important proof of principle evidence for these small molecule nucleic acid agents as potential therapeutic tools as cardioprotective agents in ischaemia-reperfusion injury.Read moreRead less
Alternative Splicing Of GLI1 And Its Role In Tumourigenesis
Funder
National Health and Medical Research Council
Funding Amount
$392,640.00
Summary
Gene expression involves the transfer of information from DNA to proteins and is mediated by a third molecule called messenger RNA (mRNA). The process is tightly controlled since unregulated gene expression is harmful and can result in diseases such as developmental disorders and cancer. The genetic information in DNA is first copied to an RNA molecule in a process called transcription. This RNA molecule then undergoes a series of maturation steps before the information it carries can be transla ....Gene expression involves the transfer of information from DNA to proteins and is mediated by a third molecule called messenger RNA (mRNA). The process is tightly controlled since unregulated gene expression is harmful and can result in diseases such as developmental disorders and cancer. The genetic information in DNA is first copied to an RNA molecule in a process called transcription. This RNA molecule then undergoes a series of maturation steps before the information it carries can be translated into a protein. One of these maturation steps involves the removal of sequences (called introns) that do not contain protein coding information from the sequences (called exons) that will be present in the mature mRNA. Some genes contain no introns while others contain 20 or more, which are dispersed throughout the gene. The removal of intron sequences from immature RNA molecules is called splicing and is carried out by a macromolecular complex that recognises the intron sequences, cuts them out of the RNA and then rejoins the RNA to make a contiguous sequence. This process has to be precise otherwise spurious sequences will be present in the mRNA, which will result in the production of abnormal proteins. In addition, for some genes mRNAs are produced that have differences in a portion of their sequence. These alternative sequences are generated by the inclusion or exclusion of alternative exons. Because, RNA splicing is critical to the production of mature mRNAs and because it can generate sequence diversity it is tightly regulated. We have recently found that expression of a cancer gene (called GLI1) is regulated in part by the use of alternative GLI1 mRNAs. Moreover, we found that the expression of one of these alternative GLI1 mRNAs is associated with skin cancer. In this project we will investigate the molecular mechanisms that regulate alternative splicing in GLI1 and identify whether changes in these mechanisms result in cancer.Read moreRead less
Role Of MicroRNAs In The Control Of MRNA Translation
Funder
National Health and Medical Research Council
Funding Amount
$360,500.00
Summary
This project studies the function of a recently discovered class of ribonucleic acid (RNA) molecules termed microRNAs (miRNAs). They appear to have very important functions in all multicellular organisms, since many of them have undergone little change over hundreds of millions of years. At present we know that miRNAs probably work by regulating the efficiency with which messenger RNAs (mRNAs) are translated into protein molecules. However we do not know how they accomplish this, or which mRNAs ....This project studies the function of a recently discovered class of ribonucleic acid (RNA) molecules termed microRNAs (miRNAs). They appear to have very important functions in all multicellular organisms, since many of them have undergone little change over hundreds of millions of years. At present we know that miRNAs probably work by regulating the efficiency with which messenger RNAs (mRNAs) are translated into protein molecules. However we do not know how they accomplish this, or which mRNAs are regulated by miRNAs. Our work to date has suggested to us that miRNAs may act in combination with one another on mRNAs, so that the effect on a given mRNA depends on just which miRNAs are present, and how abundant they are. We propose to construct a system in which the function of miRNAs can be studied in vitro, using crude cell extracts that are known to perform mRNA translation and related functions. This will, for the first time, make it possible to test miRNAs in carefully controlled conditions, and ask which steps in translation they affect. We will be able to investigate just how the pairing of miRNA and mRNA sequences determines the ability of a miRNA to act on a specific mRNA, and to confirm that a given miRNA actually does regulate a specific mRNA. To facilitate this goal, we will use three methods to isolate mRNAs that are targets of miRNA regulation. Each of these methods relies on the physical interaction of miRNA and mRNAs in cell extracts. In one method, we will attach a tag to a miRNA, and use the tag to pull out associated mRNAs. In another method, we will use an antibody to a protein that is thought to associate with all miRNAs. The antibody should pull out any mRNAs associated with the miRNA-protein complex. Finally, we will identify mRNAs that have responded to the presence of a miRNA by changing the efficiency with which they are translated. These experiments will provide essential knowledge about an extremely important biological system.Read moreRead less