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Brain metabolic changes in experimental malaria: a paradigm for the molecular mechanisms of intravascular inflammation. Malaria is endemic in countries directly to the north of Australia, as close as Papua New Guinea and East Timor. This project's findings about malaria also will have relevance to other infectious diseases of national importance. The outcomes will contribute to Australia's research reputation. We will build international links that will increase the national knowledge base and r ....Brain metabolic changes in experimental malaria: a paradigm for the molecular mechanisms of intravascular inflammation. Malaria is endemic in countries directly to the north of Australia, as close as Papua New Guinea and East Timor. This project's findings about malaria also will have relevance to other infectious diseases of national importance. The outcomes will contribute to Australia's research reputation. We will build international links that will increase the national knowledge base and research skill base. Young scientists will be trained in state-of-the-art research techniques in a cross-disciplinary environment that is the way of future biological research. The project may identify potential drug targets for malaria or other infectious diseases. The Intellectual Property will be protected and commercialised.Read moreRead less
Microparticles as effectors of microvascular alterations in brain inflammation. Cerebral malaria (CM) kills many children worldwide, but we do not understand why their small blood vessels in the brain become obstructed. We found that tiny elements detached from cell membranes, called microparticles (MP), are dramatically elevated in the blood during CM. Our results strongly suggest that these MP are important in CM development. We have found that some drugs block the release of MP and the stick ....Microparticles as effectors of microvascular alterations in brain inflammation. Cerebral malaria (CM) kills many children worldwide, but we do not understand why their small blood vessels in the brain become obstructed. We found that tiny elements detached from cell membranes, called microparticles (MP), are dramatically elevated in the blood during CM. Our results strongly suggest that these MP are important in CM development. We have found that some drugs block the release of MP and the stickiness of malaria parasites to blood vessels. Our project will tackle the conditions of MP production and define new drugs to prevent it. It also will explain how the brain becomes affected by high numbers of MP. Our results will cast new light on why the brain functions abnormally when its blood vessels become modified.Read moreRead less
Membrane excitability and cellular calcium regulation in the peripheral nervous system under different (patho)-physiological conditions and in inflammatory disease. Studies of cytokine action on neurons and muscle give new insights into functional responses of the nervous system to systemic inflammation and sepsis. In some countries, sepsis is the third most frequent cause of death following heart attack. Elucidating the pathomechanisms allows to develop therapeutic strategies. Electrophysiology ....Membrane excitability and cellular calcium regulation in the peripheral nervous system under different (patho)-physiological conditions and in inflammatory disease. Studies of cytokine action on neurons and muscle give new insights into functional responses of the nervous system to systemic inflammation and sepsis. In some countries, sepsis is the third most frequent cause of death following heart attack. Elucidating the pathomechanisms allows to develop therapeutic strategies. Electrophysiology, Ca2+ regulation and optical membrane potentiometry allow us to monitor early changes in disease on a (sub)cellular level. Experiments on Ca2+ regulation and ion channel function in muscle with different cholesterol membrane contents will help to understand pathomechanisms in high cholesterol diseases, e.g. obesity, on the membrane level long before cardiovascular effects become prominent.Read moreRead less
Elucidating the regulation of cell death by random mutagenesis of key apoptotic proteins. All organisms need to remove damaged or excessive cells. This cell death process is called apoptosis. Defects in apoptosis result in numerous diseases including cancer, and neurodegenerative and immune disorders. Determining how this process is regulated is of crucial importance for therapeutic intervention. We will utilise a powerful strategy to mutate proteins required for apoptosis so that they no longer ....Elucidating the regulation of cell death by random mutagenesis of key apoptotic proteins. All organisms need to remove damaged or excessive cells. This cell death process is called apoptosis. Defects in apoptosis result in numerous diseases including cancer, and neurodegenerative and immune disorders. Determining how this process is regulated is of crucial importance for therapeutic intervention. We will utilise a powerful strategy to mutate proteins required for apoptosis so that they no longer work, which will allow the identification of protein regions essential for cell death activity . This will lead to identification of potential drug targets to control apoptosis. Elucidating the mechanism of cell death will lead to the development of novel and improved therapies for diseases such as cancer and neurodegenerative disease.Read moreRead less
Central nervous system cytokines and morphine analgesia. Morphine remains the drug of choice for the management of moderate-to-severe pain, however its clinical effectiveness is compromised by the fact that morphine's analgesic (pain reducing) efficacy becomes less effective the more it is administered.. This project will examine how analgesic tolerance develops from a completely new approach: Namely, how stimulation of the immune system within the central nervous system is a crucial factor in t ....Central nervous system cytokines and morphine analgesia. Morphine remains the drug of choice for the management of moderate-to-severe pain, however its clinical effectiveness is compromised by the fact that morphine's analgesic (pain reducing) efficacy becomes less effective the more it is administered.. This project will examine how analgesic tolerance develops from a completely new approach: Namely, how stimulation of the immune system within the central nervous system is a crucial factor in the development of tolerance. Modulation of analgesia by the immune system has not been systematically studied and provides a potentially fertile ground for the development of new techniques in the management of clinical pain.Read moreRead less
Molecular grafting methods for design of peptide therapeutics. This project has the potential to lead to major economic benefits to Australia via royalty returns from novel drugs. Extra economic benefits derive from a reduction in the cost of treatment of diseases. The development of a new Australian developed peptide drug thus has the potential to lead to multimillion dollar savings to the Australian economy. Finally the project will provide training in state-of-the-art drug design that will e ....Molecular grafting methods for design of peptide therapeutics. This project has the potential to lead to major economic benefits to Australia via royalty returns from novel drugs. Extra economic benefits derive from a reduction in the cost of treatment of diseases. The development of a new Australian developed peptide drug thus has the potential to lead to multimillion dollar savings to the Australian economy. Finally the project will provide training in state-of-the-art drug design that will enhance Australia's pharmaceutical industry generally.Read moreRead less
Calcium signalling in neurons of the central nervous system. Understanding of the processes of cell-to-cell communication between neurons that comprise the brain and central nervous system is of primary importance to our understanding of fundamental phenomena such as voluntary and reflex movement, sensory responses and learning and memory. We would like to obtain a better understanding of how calcium controls neuronal and synaptic function. These studies will combine high-speed fluorescence ima ....Calcium signalling in neurons of the central nervous system. Understanding of the processes of cell-to-cell communication between neurons that comprise the brain and central nervous system is of primary importance to our understanding of fundamental phenomena such as voluntary and reflex movement, sensory responses and learning and memory. We would like to obtain a better understanding of how calcium controls neuronal and synaptic function. These studies will combine high-speed fluorescence imaging, electrophysiological recording, gene transfer using Adeno- and Sindbis viruses, and genetically designed and targeted biosensors to describe key "descriptors" of the calcium signals generated as neurons of the central nervous system ?talk? to each other.Read moreRead less
Hierarchical Phosphorylation of Tyrosine Hydroxylase is Dependent on the Activation Sequence of Signaling Pathways. Protein phosphorylation is a fundamental process in biology. It controls protein expression and function in all cells. Hierarchical phosphorylation is defined as the phosphorylation of a protein at one site leading to an altered phosphorylation at another site on the same protein and an altered biological outcome. We have discovered that the enzyme tyrosine hydroxylase undergoes a ....Hierarchical Phosphorylation of Tyrosine Hydroxylase is Dependent on the Activation Sequence of Signaling Pathways. Protein phosphorylation is a fundamental process in biology. It controls protein expression and function in all cells. Hierarchical phosphorylation is defined as the phosphorylation of a protein at one site leading to an altered phosphorylation at another site on the same protein and an altered biological outcome. We have discovered that the enzyme tyrosine hydroxylase undergoes a form of hierarchical phosphorylation not previously reported. Here we examine hierarchical phosphorylation in rat and human tyrosine hydroxylase and its functional consequence in intact cells. The approaches and methods developed will also be applicable to investigation of hierarchical phosphorylation in other proteins.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
Olfactory signal transduction in Drosophila melanogaster. This project will strengthen Australia's research capabilities in the areas of molecular neurobiology and neurogenetics. The project will equip students with the intellectual and technical skills needed to work in priority areas such as genomics and biotechnology, as well as in medical and agricultural research, and education. The research has possible long term applications in modifying the behaviour of insects of agricultural or medical ....Olfactory signal transduction in Drosophila melanogaster. This project will strengthen Australia's research capabilities in the areas of molecular neurobiology and neurogenetics. The project will equip students with the intellectual and technical skills needed to work in priority areas such as genomics and biotechnology, as well as in medical and agricultural research, and education. The research has possible long term applications in modifying the behaviour of insects of agricultural or medical importance. For example, by inhibiting the ability of insects to perceive specific odours it may ultimately be possible to prevent insects that carry disease from identifying target animals, or plant pests from locating their host plants.Read moreRead less