Determinants of Expression, Assembly and Function of the Noradrenaline Transporter. The noradrenaline transporter protein that is the focus of this project is important for mental health because it belongs to the family of proteins where psychostimulants, such as cocaine, and drugs used in the treatment of depression act. The project will lead to exciting advances in our understanding of how the structure of this protein controls its functions, and potentially to the design of better antidepress ....Determinants of Expression, Assembly and Function of the Noradrenaline Transporter. The noradrenaline transporter protein that is the focus of this project is important for mental health because it belongs to the family of proteins where psychostimulants, such as cocaine, and drugs used in the treatment of depression act. The project will lead to exciting advances in our understanding of how the structure of this protein controls its functions, and potentially to the design of better antidepressant drugs and to the design of drugs to prevent the effects of cocaine.Read moreRead less
Probing norepinephrine transporter (NET) structure-function. More selective drugs are needed to improve the treatment of a range of diseases including pain, depression and anxiety. This project will apply advanced molecular pharmacology approaches to better understand how the norepinephrine transporter functions and where small molecules and conotoxins bind to inhibit its activity.
Fish venom as a model system for the molecular evolution of defensive toxins. The key aim of this study is to undertake a thorough investigation of venoms found in distinct fish lineages, including enigmatic species such as venomous and medically important species such as the stonefish. By characterising the biodiversity of toxins found in the venoms of different fish, the evolutionary history of venom in this major vertebrate lineage can be revealed. The investigations proposed here will also d ....Fish venom as a model system for the molecular evolution of defensive toxins. The key aim of this study is to undertake a thorough investigation of venoms found in distinct fish lineages, including enigmatic species such as venomous and medically important species such as the stonefish. By characterising the biodiversity of toxins found in the venoms of different fish, the evolutionary history of venom in this major vertebrate lineage can be revealed. The investigations proposed here will also determine the functional activities of different venoms and their components. This will not only help the understanding of the medical consequences of the annual thousands of fish envenomings but also explore a largely unstudied resource for the discovery of new pharmacological diagnostics and therapeutics.Read moreRead less
Evolutionary venomics: Venom system diversification in the animal kingdom. This proposal represents a tremendous opportunity for biodiscovery from the Australian toxic fauna. This will be achieved through the researcher's unique approach of investigating previously unmapped venom systems for divergent, bioactive proteins. An understanding of venomous animal protein evolution has practical implications for the treatment of envenomations - an enormous problem in Australia - as well as great pot ....Evolutionary venomics: Venom system diversification in the animal kingdom. This proposal represents a tremendous opportunity for biodiscovery from the Australian toxic fauna. This will be achieved through the researcher's unique approach of investigating previously unmapped venom systems for divergent, bioactive proteins. An understanding of venomous animal protein evolution has practical implications for the treatment of envenomations - an enormous problem in Australia - as well as great potential in drug discovery and other commercial applications. This project will provide Australian graduate and post-graduate students with finely tuned skills in cutting edge methodological techniques and a fluent understanding of molecular evolution, preparing them to be internationally competitive scientists.Read moreRead less
Characterisation of monoaminergic transmission in Central Amygdala. This project will identify the distribution and function of dopamine, serotonin and noradrenalin receptors on the various cell types and their inputs, in the medial, lateral and capsular divisions of Central Amygdala (CeA). We will test for tonic endogenous activation of monoaminergic receptors and synaptic release from electrically stimulated fibers terminating in CeA. Using paired recordings and calcium imaging, we will invest ....Characterisation of monoaminergic transmission in Central Amygdala. This project will identify the distribution and function of dopamine, serotonin and noradrenalin receptors on the various cell types and their inputs, in the medial, lateral and capsular divisions of Central Amygdala (CeA). We will test for tonic endogenous activation of monoaminergic receptors and synaptic release from electrically stimulated fibers terminating in CeA. Using paired recordings and calcium imaging, we will investigate intracellular mechanisms underlying monoamine receptor mediated effects. These findings when correlated with published behavioural studies will provide greater understanding of the role of the divisions of CeA and the inputs they receive, in the function of the amygdala.Read moreRead less
Activation mechanisms of Cys-loop ion channel receptors. This proposal will employ a cutting edge approach to reveal fundamental new insights into the ways that proteins work. The information and technology developed here will broaden and strengthen Australia's research expertise across a number of basic scientific disciplines. The results will also have relevance to human health. Cys-loop ligand-gated receptors have an essential role in brain function and are targets for many therapies and drug ....Activation mechanisms of Cys-loop ion channel receptors. This proposal will employ a cutting edge approach to reveal fundamental new insights into the ways that proteins work. The information and technology developed here will broaden and strengthen Australia's research expertise across a number of basic scientific disciplines. The results will also have relevance to human health. Cys-loop ligand-gated receptors have an essential role in brain function and are targets for many therapies and drugs of abuse. New insights into how biological ligands and drugs affect ion channel structure and function may lead to novel therapeutic opportunities and improved drug structure predictions.Read moreRead less
CHARGED LIPOSACCHARIDE BASED DRUG DELIVERY SYSTEM. Complexation of a drug with lipid and/or sugar units represents one of the most important of the strategies being investigated in this burgeoning field. Increasing the lipid solubility of a hydrophilic compound has been established as an important factor in improving its absorption as it is necessary for passive transport across intestinal mucosal membranes. The role of sugar unit is very important: (i) it modifies the physico-chemical propertie ....CHARGED LIPOSACCHARIDE BASED DRUG DELIVERY SYSTEM. Complexation of a drug with lipid and/or sugar units represents one of the most important of the strategies being investigated in this burgeoning field. Increasing the lipid solubility of a hydrophilic compound has been established as an important factor in improving its absorption as it is necessary for passive transport across intestinal mucosal membranes. The role of sugar unit is very important: (i) it modifies the physico-chemical properties (solubility), (ii) utilizes active transport systems (e.g. Glucose transport) and (iii) target the compound - "MAGIC BULET" (Lewis X analogues - damaged cells). There is no limit to the areas of medicine and public health that would benefit from revolutionary new technology in these 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
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