Exploring Roles For MicroRNAs In Cancer Using Bioinformatics And Gene Expression Tools.
Funder
National Health and Medical Research Council
Funding Amount
$292,639.00
Summary
microRNAs are newly discovered chemicals that were the subject of the 2006 Nobel Prize in Medicine. These chemicals decrease the amount of specific molecular ‘targets’ in cells, and play an important role in cancer. Currently we do not understand how these chemicals choose their targets, and we propose to use a computer-based approach to discover how they affect genes in cancer. This will improve our understanding of cancer and thereby lead to the discovery of novel anti-cancer therapies.
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
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
Post Transcriptional Regulation Of Plasminogen Activator Inhibitor Type 2 Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$318,000.00
Summary
The process of wound healing, cell migration and the spread of cancers requires the recruitment of specialised proteases to the cell surface . These proteases act to degrade other proteins, mainly in the extracellular space, which in turn allows cells to move around, wounds to close, and blood clots to disappear. The plasminogen activating system is one of the enzyme systems involved in these events. One of the proteases that cleaves plasminogen to its active form, plasmin, is urokinase (u-PA) a ....The process of wound healing, cell migration and the spread of cancers requires the recruitment of specialised proteases to the cell surface . These proteases act to degrade other proteins, mainly in the extracellular space, which in turn allows cells to move around, wounds to close, and blood clots to disappear. The plasminogen activating system is one of the enzyme systems involved in these events. One of the proteases that cleaves plasminogen to its active form, plasmin, is urokinase (u-PA) and the activity of u-PA is regulated by its natural inhibitor called plasminogen activator inhibitor type 2 (PAI-2). u-PA is strongly implicated in the progression of metastatic cancer and high levels of PAI-2 relative to u-PA is regularly seen as a positive prognostic indicator for metastatic cancer. In this situation, PAI-2 acts to limit the activity of u-PA thereby restricting the migration potential of the cancer. PAI-2 is unusual because it exists both inside and outside the cell. Outside the cell, PAI-2 acts to inhibit u-PA activity, while inside the cell, PAI-2 also plays a role in the inhibition of cell growth and differentiation. It is therefore important to understand how the production of PAI-2 is regulated in cells. A significant component of PAI-2 regulation occurs post-transcriptionally, particularly at the level of mRNA stability. We have identified some of the proteins that bind to PAI-2 mRNA and influence its longevity in the cell. This project aims to further undertand how these as well as other PAI-2 mRNA binding proteins influence the expression of the PAI-2 gene.Read moreRead less
Investigation Of 5-methylcytosine And MicroRNA Function In Eukaryotic RNA
Funder
National Health and Medical Research Council
Funding Amount
$311,991.00
Summary
It is hypothesised that 5-methylcytosine in RNA represents a novel regulatory code affecting transcriptome utilisation in ways currently hidden from view. To unravel this code and its (patho)- physiological role(s), this study proposes to generate and interpret comprehensive transcriptome-scale maps of 5-methylcytosine in a range of cellular contexts chosen to reveal links to cellular differentiation, growth, and malignant transformation.