Control of the use of DNA, gene expression, is vital to all living organisms, especially in development and disease. The information in the genes is transferred to an intermediate molecule, mRNA, in a process called transcription. The genetic information in the mRNA is subsequently used, in the process called translation, to make the protein encoded by the original gene. The switching on and off of DNA appears to be most frequently controlled at the transcription step but recently it has become ....Control of the use of DNA, gene expression, is vital to all living organisms, especially in development and disease. The information in the genes is transferred to an intermediate molecule, mRNA, in a process called transcription. The genetic information in the mRNA is subsequently used, in the process called translation, to make the protein encoded by the original gene. The switching on and off of DNA appears to be most frequently controlled at the transcription step but recently it has become apparent that there are many post-transcriptional events that govern how efficiently the genetic information is ultimately converted to protein molecules. In this project we will investigate the molecular mechanisms of several proteins, heterogeneous nuclear ribonucleoproteins (hnRNPs), that appear to play regulatory roles in many of these steps. These proteins appear to affect the longevity and replication of cells, the important chemical changes that take place in RNA after it is transcribed and before it is translated, the movement of the modifed RNAs through the cell and the efficiency of translation. Because of these central functions they are involved in development of tissues such as the brain, and in diseases including lung, skin and brain cancers, and rheumatoid arthritis. In this project we will focus on two RNA molecules, one vital for myelination in the central nervous system and the other for memory.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0453400
Funder
Australian Research Council
Funding Amount
$110,040.00
Summary
The Roboocyte™: a medium-throughput, secondary functional, screening facility. Changes in ion channel function have been implicated in a wide variety of human diseases. For this reason many researchers are studying ion channels to understand how they work and how they can develop new drug treatments. The slowest step in evaluating the biological activity of compounds is testing them against the ion channels and the current technology requires much tedious manual handling and extensive operator e ....The Roboocyte™: a medium-throughput, secondary functional, screening facility. Changes in ion channel function have been implicated in a wide variety of human diseases. For this reason many researchers are studying ion channels to understand how they work and how they can develop new drug treatments. The slowest step in evaluating the biological activity of compounds is testing them against the ion channels and the current technology requires much tedious manual handling and extensive operator expertise. The Roboocyte facility will triple testing productivity by allowing for the rapid and automated screening of large libraries of compounds. Such a facility will be unique to the Southern Hemisphere.Read moreRead less
Control of cell fate decisions in neurogenesis: use of embryonic stem cells to investigate key signalling systems and gene expression programs. Human embryonic stem cells (hESC) have the potential to provide an unlimited source of specific subtypes of human neurons for basic studies in neuroscience and biomedical applications. The use of hESC is limited at present by a lack of control over lineage commitment during differentiation in vitro. This project will use engineered reporter hESC lines t ....Control of cell fate decisions in neurogenesis: use of embryonic stem cells to investigate key signalling systems and gene expression programs. Human embryonic stem cells (hESC) have the potential to provide an unlimited source of specific subtypes of human neurons for basic studies in neuroscience and biomedical applications. The use of hESC is limited at present by a lack of control over lineage commitment during differentiation in vitro. This project will use engineered reporter hESC lines to investigate which cell signalling pathways and gene expression programs are involved in controlling cell fate. The project will result in improved protocols for hESC differentiation allowing enrichment of cultures with specific neuronal subtypes, and significant advances in the understanding of neuronal lineage commitment and maturation during brain development. Read moreRead less
A major feature of tumour progression and cardiac hypertrophy (enlarged heart) is accelerated cell growth and protein synthesis. Moreover, increased synthesis of ribosomes (the protein synthetic machinery) is associated with malignancy and hypertrophy suggesting that it may play a causal role in tumour formation and cardiac disease. In support of this, specific inhibitors of both ribosome biogenesis and function are extremely effective at inhibiting the growth of some tumours and vascular smooth ....A major feature of tumour progression and cardiac hypertrophy (enlarged heart) is accelerated cell growth and protein synthesis. Moreover, increased synthesis of ribosomes (the protein synthetic machinery) is associated with malignancy and hypertrophy suggesting that it may play a causal role in tumour formation and cardiac disease. In support of this, specific inhibitors of both ribosome biogenesis and function are extremely effective at inhibiting the growth of some tumours and vascular smooth muscle. This study will examine the mechanisms that regulate ribosome synthesis. Specifically it focuses on a transcription factor termed UBF whose activity we think is critical for the regulation of the synthesis of the ribosomal RNA, the catalytic backbone of the ribosomes. Understanding the molecular mechanism(s) controlling UBF function will lead to a better comprehension of how cells modulate synthesis of functional ribosomes and how this process is deregulated during disease states associated with deregulated protein synthesis and growth such as cardiac hypertrophy and cancer.Read moreRead less
Molecular neurobiology of the GABAB receptor: Studies of heteromeric receptor function and signalling. The G protein-coupled receptor (GPCR) for the inhibitory transmitter gamma- aminobutyric acid (GABA) is a unique heterodimer. Molecular analyses will be undertaken to provide insights into its signalling mechanisms and functional regulation. Investigations employing point mutant and chimeric receptors will analyse how ligand binding to the extracellular domain of the GABA-BR1 subunit triggers ....Molecular neurobiology of the GABAB receptor: Studies of heteromeric receptor function and signalling. The G protein-coupled receptor (GPCR) for the inhibitory transmitter gamma- aminobutyric acid (GABA) is a unique heterodimer. Molecular analyses will be undertaken to provide insights into its signalling mechanisms and functional regulation. Investigations employing point mutant and chimeric receptors will analyse how ligand binding to the extracellular domain of the GABA-BR1 subunit triggers G protein-coupling to the intracellular portion of the GABA-BR2 subunit. Focus will be on different modes of GPCR signalling, including constitutive activity and roles for membrane and cytosolic regulatory proteins. Targeted studies of GABAB receptor subunits will provide new information on the mechanistic regulation of GPCR signalling.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0883078
Funder
Australian Research Council
Funding Amount
$356,000.00
Summary
Liquid Chromatography Tandem Mass Spectrometry Steroid Analysis Facility. This first of a new generation of ultra-sensitive analytical mass spectrometers for small molecules will be established as a national assay facility allowing all Australian researchers open access to a new dimension of highly accurate and simultaneous measurements of multiple bodily chemicals such as steroids, vitamins and hormones. It is crucial to developing new knowledge in basic, developmental and pathological cell bio ....Liquid Chromatography Tandem Mass Spectrometry Steroid Analysis Facility. This first of a new generation of ultra-sensitive analytical mass spectrometers for small molecules will be established as a national assay facility allowing all Australian researchers open access to a new dimension of highly accurate and simultaneous measurements of multiple bodily chemicals such as steroids, vitamins and hormones. It is crucial to developing new knowledge in basic, developmental and pathological cell biology and for underpinning commercial developments of new molecular targets for therapeutic drugs for many diseases including cancer, cardiovascular disease and reproductive disorders. This facility is pivotal to maintaining international competitiveness in many areas of biological research in national priority areas.Read moreRead less
Alpha-Conotoxins: Selective Probes For Nicotinic Receptor Subtype Structure And Function. Marine snails from the waters off the Australian coast produce an amazing variety of mini-proteins in their venoms called conotoxins that they use to capture prey. These conotoxins bind very specifically to receptors in our body associated with the transmission of nerve signals. We will use natural and synthetically modified conotoxins to selectively block particular types of neuronal 'receptors' to gain a ....Alpha-Conotoxins: Selective Probes For Nicotinic Receptor Subtype Structure And Function. Marine snails from the waters off the Australian coast produce an amazing variety of mini-proteins in their venoms called conotoxins that they use to capture prey. These conotoxins bind very specifically to receptors in our body associated with the transmission of nerve signals. We will use natural and synthetically modified conotoxins to selectively block particular types of neuronal 'receptors' to gain a greater understanding of how the nervous system functions. This knowledge will help in the design of new drugs to treat a variety of diseases and disorders. Essentially we will use a chemical armoury developed by the cone snail to design state-of-the-art mini-protein drugs.Read moreRead less
Conotoxins: Novel probes for ion channel structure and function. Voltage-dependent and ligand-gated ion channels are intrinsic membrane proteins that play a central role in communication in excitable cells, particularly in the nervous system. The primary goals of this project are (i) to define at a molecular level, the structural and functional determinants of ion channel/conotoxin interactions and (ii) develop new probes that advance neurophysiological research. The diversity and distribution o ....Conotoxins: Novel probes for ion channel structure and function. Voltage-dependent and ligand-gated ion channels are intrinsic membrane proteins that play a central role in communication in excitable cells, particularly in the nervous system. The primary goals of this project are (i) to define at a molecular level, the structural and functional determinants of ion channel/conotoxin interactions and (ii) develop new probes that advance neurophysiological research. The diversity and distribution of ion channel types and subtypes being uncovered through the use of molecular biology and conotoxin probes presents an exciting opportunity for the future development of novel ion channel therapeutics.Read moreRead less
New modulators of voltage-gated sodium channel subtypes from Australian Tarantula venoms. The venoms of Australian tarantula spiders provide a unique and untapped source of bioactive molecules. From a large stock of venom, and in collaboration with Australian pharmaceutical company Xenome, we will develop a comprehensive library of venom components suitable for drug screening. Potential national benefits from this work include a huge reduction in the healthcare bill deriving from a new treatmen ....New modulators of voltage-gated sodium channel subtypes from Australian Tarantula venoms. The venoms of Australian tarantula spiders provide a unique and untapped source of bioactive molecules. From a large stock of venom, and in collaboration with Australian pharmaceutical company Xenome, we will develop a comprehensive library of venom components suitable for drug screening. Potential national benefits from this work include a huge reduction in the healthcare bill deriving from a new treatment for pain, as well as substantial royalty returns from drugs sales. Discoveries from the program are also likely to lead to an enhancement in Australia's reputation in the neurosciences and to the development of new diagnostic research tools. The major community benefit will be a reduction in the suffering of chronic pain patients.Read moreRead less
Defining mechanisms of action of novel alpha-conotoxins at nicotinic receptor-channels. Marine snails from the waters off the Australian coast produce an amazing variety of mini-proteins in their venoms called conotoxins that they use to capture prey. These conotoxins bind very specifically to receptors in our body associated with the transmission of nerve signals. We will use natural and synthetically modified conotoxins to selectively block particular types of neuronal 'receptors' to gain a gr ....Defining mechanisms of action of novel alpha-conotoxins at nicotinic receptor-channels. Marine snails from the waters off the Australian coast produce an amazing variety of mini-proteins in their venoms called conotoxins that they use to capture prey. These conotoxins bind very specifically to receptors in our body associated with the transmission of nerve signals. We will use natural and synthetically modified conotoxins to selectively block particular types of neuronal 'receptors' to gain a greater understanding of how the nervous system functions. This knowledge will help in the design of new drugs to treat a variety of diseases and disorders. Essentially we will use a chemical armoury developed by the cone snail to design state-of-the-art mini-protein drugs.Read moreRead less