Identifying Target Molecules Regulated By Nuclear Retention In Cancer And Development
Funder
National Health and Medical Research Council
Funding Amount
$267,173.00
Summary
Human DNA contains approximately 30000 genes; only twice as many as worms and flies, ten times as many as bacteria, and fewer than rice. Humans, however have considerably more complexity than these lower organisms. What are the factors responsible for the additional complexity? In the simplest scenario, one gene is transcribed to produce one message (mRNA), which is the blueprint for producing one protein. We now know that there are numerous mechanisms that potentially allow many different prote ....Human DNA contains approximately 30000 genes; only twice as many as worms and flies, ten times as many as bacteria, and fewer than rice. Humans, however have considerably more complexity than these lower organisms. What are the factors responsible for the additional complexity? In the simplest scenario, one gene is transcribed to produce one message (mRNA), which is the blueprint for producing one protein. We now know that there are numerous mechanisms that potentially allow many different proteins to be made from one gene. Also, it is the decisions about which gene will be made ( expressed ) into protein where and when in development, that is critical for our complexity. The control of gene expression is thus fundamental to all cellular processes and many diseases such as cancer and metabolic disorders are associated with some aspect of aberrant gene expression. The production of mRNA from DNA occurs in the human cell nucleus. The nucleus is not simply a bag of DNA, in fact, many important nuclear factors are organised into sub-nuclear bodies . Recently we discovered a novel sub-nuclear body, the paraspeckle and have been identifying its components and their function. Paraspeckles are involved in a previously undiscovered mechanism of the control of gene expression. Here, certain mRNA molecules are trapped in the nucleus until a signal is received from elsewhere in the cell, which causes the mRNA to be released and protein to be made. This Rapid Release Nuclear Retention mechanism effectively allows the quick production of specific proteins to be made on demand. In this project we propose to use cutting edge molecular and cell biology techniques to identify the special mRNA molecules that are trapped in paraspeckles in cancer cells. This will increase our understanding about the molecular details of this process, ultimately leading to potential uses in gene therapy, and should result in the discovery of important targets for cancer treatment.Read moreRead less
Post Transcriptional Regulation Of The Plasminogen Activator Inhibitor Type 2 Gene
Funder
National Health and Medical Research Council
Funding Amount
$241,527.00
Summary
The process of wound healing, removal of blood clots, cell migration and the metastatic spread of cancers requires the recruitment of specialised proteases. These proteases act primarily to degrade other proteins, mainly in the extracellular space, which in turn allow cells to move around, wounds to close, and blood clots to disappear. The plasminogen activating system is one of the most important enzyme systems involved in these events. One of the proteases that cleaves plasminogen to its activ ....The process of wound healing, removal of blood clots, cell migration and the metastatic spread of cancers requires the recruitment of specialised proteases. These proteases act primarily to degrade other proteins, mainly in the extracellular space, which in turn allow cells to move around, wounds to close, and blood clots to disappear. The plasminogen activating system is one of the most important enzyme systems involved in these events. One of the proteases that cleaves plasminogen to its active form, plasmin, is urokinase (u-PA). Plasminogen activator inhibitor type 2 (PAI-2) is a serine protease inhibitor that inhibits u-PA activity. The degree of u-PA activity therefore depends on the relative levels of u-PA and PAI-2. In addition to controlling u-PA activity, PAI-2 also influences intracellular events including cell proliferation, differentiation and apoptosis. PAI-2 protein and mRNA levels are substantially modulated by many cytokines and growth factors. This project addresses the molecular mechanisms underlying the regulation of PAI-2 gene expression. We have recently shown that a significant degree of PAI-2 regulation occurs at the level of PAI-2 mRNA stability, and we have identified two regions within the PAI-2 mRNA that play a role in this process. Both regions provide binding sites for cellular proteins. We have identified one of these binding proteins to be HuR, a protein that has recently been shown to control the stability of other mRNAs. The specific aims of this project are firstly, to determine the role of HuR in the control of PAI-2 mRNA stability, and secondly, to clone a characterise the other PAI-2 mRNA binding proteins we have identifed. An understanding of how cells modulate levels of PAI-2 mRNA will significantly add to the broader field of gene regulation and may also provide new clues to influence PAI-2 levels in the body.Read moreRead less
microRNA are non-coding RNAs with fundamental functions in biology and emerging roles in disease. Hundreds of microRNA have been found and they control gene expression by destroying RNA or controlling their translation into cellular proteins. We will characterise their mechanisms of action and the cellular factors that are involved. Understanding the way microRNA work is a key question in gene regulation research and will aid the development of therapeutic strategies invovling small RNA.
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
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0453920
Funder
Australian Research Council
Funding Amount
$108,680.00
Summary
Molecular diagnostics based on real-time polymerase chain reactions for emerging tropical infectious diseases aimed at protecting Australia from invasive diseases. The project aims to use the technique of real-time polymerase chain reaction to rapidly detect and quantify the organisms associated with emerging and re-emerging infectious diseases of man and animals. It will also be used to determine related gene expression.
The equipment will be used to support a wide range of projects that req ....Molecular diagnostics based on real-time polymerase chain reactions for emerging tropical infectious diseases aimed at protecting Australia from invasive diseases. The project aims to use the technique of real-time polymerase chain reaction to rapidly detect and quantify the organisms associated with emerging and re-emerging infectious diseases of man and animals. It will also be used to determine related gene expression.
The equipment will be used to support a wide range of projects that require the detection of specific RNA or DNA and it will allow the rapid, cost effective and efficient processing of either RNA or DNA from large numbers of samples. Minor variations in organisms will be detected using this equipment.
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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.
A Comprehensive Analysis Of Myb Target Genes Involved In Myelopoiesis And Myeloid Transformation
Funder
National Health and Medical Research Council
Funding Amount
$511,294.00
Summary
The MYB gene is essential for both normal blood cell formation and the growth of leukaemia cells. It acts by switching other genes (target genes) on and off. This project aims to advance our understanding of how MYB functions, by carrying out a comprehensive search for MYB target genes. In particular it will focus on target genes that help explain MYB's ability to control cellular growth and maturation. Some of these target genes may provide leads for future anti-cancer drug development.
Post-transcriptional Regulation Of Plasminogen Activator Inhibitor 2 Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$508,838.00
Summary
Plasminogen activator inhibitor type 2 (PAI-2) is a protease inhibitor that has intracellular and extracellular functions. The PAI-2 gene is highly regulated at the level of PAI-2 mRNA stability. We have identified regions within the PAI-2 transcript essential for this regulation and a number of novel proteins that engage these regions. This project is aimed at understanding how these and other proteins control PAI-2 expression at the mRNA level.
Transcriptional control of antigenic variation in the malaria parasite Plasmodium falciparum. Malaria is a major health concern for the Australian Defence Personnel recently deployed in East Timor, Afghanistan and the Solomon Islands and is endemic in our immediate neighbours Indonesia and Papua New Guinea. Australia is susceptible to malaria and climate change could extend the mosquitos range to large population centres of Northern Australia causing malaria in Australia. This study would clarif ....Transcriptional control of antigenic variation in the malaria parasite Plasmodium falciparum. Malaria is a major health concern for the Australian Defence Personnel recently deployed in East Timor, Afghanistan and the Solomon Islands and is endemic in our immediate neighbours Indonesia and Papua New Guinea. Australia is susceptible to malaria and climate change could extend the mosquitos range to large population centres of Northern Australia causing malaria in Australia. This study would clarify how malaria parasites evade the host's immune response and help to protect Australia by providing drug targets for the control of this invasive disease.Read moreRead less
Molecular Mechanisms For The Cell-type Specific Regulation Of The Tissue-type Plasminogen Activator Gene
Funder
National Health and Medical Research Council
Funding Amount
$490,500.00
Summary
Tissue-type plasminogen activator (t-PA) is an important enzyme that is widely known for its ability to remove blood clots. More recently, t-PA has been shown to influence memory development and under pathological conditions can promote neuronal cell death. t-PA is produced by many cells including the endothelial cells that line the blood vessels, fibroblasts, as well as cells within the central nervous system. The t-PA gene is regulated very differently in these cell types and this project will ....Tissue-type plasminogen activator (t-PA) is an important enzyme that is widely known for its ability to remove blood clots. More recently, t-PA has been shown to influence memory development and under pathological conditions can promote neuronal cell death. t-PA is produced by many cells including the endothelial cells that line the blood vessels, fibroblasts, as well as cells within the central nervous system. The t-PA gene is regulated very differently in these cell types and this project will address the mechanisms underlying the cell-type specific regulation of the t-PA gene. Endothelial cells, fibroblasts and neuronal cell cultures will be used to study the regulation of t-PA expression. Information gained will not only add to the understanding of the broader field of gene regulation, but may also provide clues to manipulate the expression of the t-PA gene in different cells.Read moreRead less