Targeted development of dual action antitumour and antiangiogenic agents using differential and functional proteomics. There is an enormous need to develop more effective and less toxic therapeutic approaches to reduce the social and economic burden of cancer. The recent identification of small molecules that can act by both destroying cancer cells and the blood vessels that carry nutrients to them has provided a unique opportunity to define the pathways involved in the action of these agents in ....Targeted development of dual action antitumour and antiangiogenic agents using differential and functional proteomics. There is an enormous need to develop more effective and less toxic therapeutic approaches to reduce the social and economic burden of cancer. The recent identification of small molecules that can act by both destroying cancer cells and the blood vessels that carry nutrients to them has provided a unique opportunity to define the pathways involved in the action of these agents in order to develop more potent drug analogues. Development of these molecules will involve a collaborative and multidisciplinary link with our industry partner and the use of frontier technologies that may lead to improved health and economic outcomes for Australia. Read moreRead less
A redox sensor and triple receptor function for guanylyl cyclase. Nitric oxide (NO) protects from blood vessel spasms and clot formation. Conversely, insufficient NO occurs in cardiovascular disease. Life-saving drugs like glycerol trinitrate supply more NO to blood vessels, however these drugs are limited in their action when their target protein (NOGC) is decreased or defective, eg. in hypertension or arteriosclerosis. We have elucidated the reason for this defect and simultaneously discovered ....A redox sensor and triple receptor function for guanylyl cyclase. Nitric oxide (NO) protects from blood vessel spasms and clot formation. Conversely, insufficient NO occurs in cardiovascular disease. Life-saving drugs like glycerol trinitrate supply more NO to blood vessels, however these drugs are limited in their action when their target protein (NOGC) is decreased or defective, eg. in hypertension or arteriosclerosis. We have elucidated the reason for this defect and simultaneously discovered an entirely novel group of drugs which activate NOGC without NO. Impressively, these drugs are most effective in diseased blood vessels. The aim is the development of novel blood pressure lowering/anti-anginal drugs with higher effectiveness and less side-effects because they work in an entirely new way.Read moreRead less
Novel insecticidal neurotoxins from Australian spider venoms. Insecticidal toxins have considerable potential as novel biopesticides to combat the evolution of widespread insect resistance to classical chemical pesticides. This problem is increasing both in Australia and internationally. This study aims to isolate and pharmacologically characterise potent and selective insecticidal neurotoxins from Australian arachnids. Our laboratories will isolate neurotoxins from spider venoms, determine thei ....Novel insecticidal neurotoxins from Australian spider venoms. Insecticidal toxins have considerable potential as novel biopesticides to combat the evolution of widespread insect resistance to classical chemical pesticides. This problem is increasing both in Australia and internationally. This study aims to isolate and pharmacologically characterise potent and selective insecticidal neurotoxins from Australian arachnids. Our laboratories will isolate neurotoxins from spider venoms, determine their selectivity in insect and mammal bioassays, determine their primary and tertiary structures, and investigate their structure-function relationships by electrophysiological techniques. These functional and structural data will allow the future engineering, by molecular or synthetic procedures, of viral biopesticide analogues with increased potency, stability and selectivity.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
Synthetic derivatives of capsaicin and gingerols as analgesics acting at the vanilloid receptor. This project aims to prepare alpha-hydroxyketones and gingerol derivatives acting at vanilloid (VR1) receptor with potential analgesic activity. These compounds will be tested for their ability to activate the VR1 receptor, desensitize the receptor and release neuropeptides associated with pain pathways. The development of these novel compounds will contribute towards understanding the mechanisms of ....Synthetic derivatives of capsaicin and gingerols as analgesics acting at the vanilloid receptor. This project aims to prepare alpha-hydroxyketones and gingerol derivatives acting at vanilloid (VR1) receptor with potential analgesic activity. These compounds will be tested for their ability to activate the VR1 receptor, desensitize the receptor and release neuropeptides associated with pain pathways. The development of these novel compounds will contribute towards understanding the mechanisms of VR1 receptor activation and provide information on how the VR1 receptor is regulated. We will determine and compare neurotoxicity of these compounds to capsaicin which is known to possess neurotoxic activity. The outcome of this project may result in effective agents for better pain management.
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Common hot spots in protein-activated GPCRs enable discovery of new ligands for mapping of G-protein signalling pathways. This project will teach researchers and industry how to more rapidly discover new compounds for development into medicines, and how to design them with reduced side effects. This interdisciplinary research will provide excellent training for scientists in chemistry, pharmacology, biochemistry and biotechnology. It will advance fundamental science at the chemistry-biology inte ....Common hot spots in protein-activated GPCRs enable discovery of new ligands for mapping of G-protein signalling pathways. This project will teach researchers and industry how to more rapidly discover new compounds for development into medicines, and how to design them with reduced side effects. This interdisciplinary research will provide excellent training for scientists in chemistry, pharmacology, biochemistry and biotechnology. It will advance fundamental science at the chemistry-biology interface, attract international interest from researchers, students, and companies, with potential for translational and commercial outcomes. New drug leads and information on how important drug targets communicate with different intracellular signalling pathways has potential to impact on National Research Priorities of good health and building Australian industry.Read moreRead less
Molecular Mechanisms Underlying G Protein Coupled Receptor Signaling
Funder
National Health and Medical Research Council
Funding Amount
$596,956.00
Summary
The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein-coupled r ....The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein-coupled receptors, the transmission of the message to the interior of the cell involves yet another protein called G protein. These receptors are the most abundant type of cell surface receptors and form the targets for nearly 50% of currently used therapeutic drugs. It is, therefore, extremely important to unravel how each of these components works, and in particular to know how they work in living cells. This project utilizes state-of-the-art methodologies to examine interactions between receptors and their cognate G proteins, in living cells and in real-time. The work will answer fundamental questions about the nature of G protein-coupled receptor signaling and will aid in the future development of more effective therapeutic agents.Read moreRead less