Investigating the functional interaction between vasopressin and angiotensin receptors. Kidney disease resulting from diabetes is a major health issue for Australians, and indigenous Australians in particular. This project aims to enable improved therapies to be developed, as well as better inform doctors regarding the use of potential combinations of existing pharmaceuticals to treat this condition.
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
Discovering novel allosteric probes of muscarinic acetylcholine receptors. This project aims at fostering novel approaches to selectively target vital receptors in the human body, the muscarinic acetylcholine receptors (mAChRs). By harnessing the design of receptor mutations, compounds synthesis and fluorescent imaging, the project expects to develop new pharmacological tools for a family of receptors essential for the life of all vertebrates. By enriching our understanding of this family of rec ....Discovering novel allosteric probes of muscarinic acetylcholine receptors. This project aims at fostering novel approaches to selectively target vital receptors in the human body, the muscarinic acetylcholine receptors (mAChRs). By harnessing the design of receptor mutations, compounds synthesis and fluorescent imaging, the project expects to develop new pharmacological tools for a family of receptors essential for the life of all vertebrates. By enriching our understanding of this family of receptor, the project expects to provide significant benefits to the research field by impacting on future drug discovery efforts, not only at mAChRs, but at other structurally related receptors.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.
How lipid binding proteins shape the activity of nuclear hormone receptors. This project aims to explore how a family of lipid binding proteins control organ specific activation of nuclear receptors – receptors that play a key role in generating energy and are critical for life. The project will employ chemical, molecular, cell biology approaches to generate new knowledge about lipid binding protein-receptor interactions and how these complexes dictate receptor activation. The outcomes could pro ....How lipid binding proteins shape the activity of nuclear hormone receptors. This project aims to explore how a family of lipid binding proteins control organ specific activation of nuclear receptors – receptors that play a key role in generating energy and are critical for life. The project will employ chemical, molecular, cell biology approaches to generate new knowledge about lipid binding protein-receptor interactions and how these complexes dictate receptor activation. The outcomes could provide a roadmap to design drugs that interact with the right protein in the right tissue and in doing so dramatically enhance drug specificity. This will benefit the success of drug treatments which require stimulation of a therapeutic response at a target site, and avoidance of potentially toxic activity at other locations.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
Stabilising biased allosteric G protein-coupled receptor conformations. This project aims to develop and identify molecules that can stabilise distinct calcium sensing receptor (CaSR) conformations. The CaSR is a G protein-coupled receptor (GPCR) vertebrates need to live. GPCRs are responsible for virtually all (patho)physiological processes. They are structurally very flexible, but this has hindered their structural determination. Developing and validating the proposed molecules should help fut ....Stabilising biased allosteric G protein-coupled receptor conformations. This project aims to develop and identify molecules that can stabilise distinct calcium sensing receptor (CaSR) conformations. The CaSR is a G protein-coupled receptor (GPCR) vertebrates need to live. GPCRs are responsible for virtually all (patho)physiological processes. They are structurally very flexible, but this has hindered their structural determination. Developing and validating the proposed molecules should help future structural studies of an important GPCR. The project expects to enhance understanding of the structure and function of the CaSR and ultimately of the GPCR superfamily, which will ultimately lead to opportunities to discover new drugs.Read moreRead less
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
Understanding the Cellular Pathways of Nuclear Receptor Activation. The success of drug treatment depends critically on specificity, i.e., stimulation of a therapeutic response at a target site, and avoidance of activity at other (potentially toxic) locations. This project aims to explore how drug interactions with binding proteins in the cytosol can induce nuclear transport and tissue specific activation of nuclear receptors - a major drug target. The project intends to employ molecular, struct ....Understanding the Cellular Pathways of Nuclear Receptor Activation. The success of drug treatment depends critically on specificity, i.e., stimulation of a therapeutic response at a target site, and avoidance of activity at other (potentially toxic) locations. This project aims to explore how drug interactions with binding proteins in the cytosol can induce nuclear transport and tissue specific activation of nuclear receptors - a major drug target. The project intends to employ molecular, structural and cell biology approaches to map drug-binding protein-receptor interactions and to determine how the structure of these complexes dictates receptor activation. The data could provide a roadmap to design drugs that interact with the right protein in the right tissue and in doing so dramatically enhance drug specificity.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