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
Exploitation of a Novel Drug Target for Controlling Animal Trypanosomiasis. Trypanosomiasis greatly reduces livestock productivity in countries where it is endemic and is a threat to livestock and native wildlife in countries such as Australia where it is exotic but there is a risk of entry. New trypanocidal drugs with different modes of action are urgently needed to overcome growing resistance. This project aims to characterise trypanosome tubulin and, with this information, produce new tubulin ....Exploitation of a Novel Drug Target for Controlling Animal Trypanosomiasis. Trypanosomiasis greatly reduces livestock productivity in countries where it is endemic and is a threat to livestock and native wildlife in countries such as Australia where it is exotic but there is a risk of entry. New trypanocidal drugs with different modes of action are urgently needed to overcome growing resistance. This project aims to characterise trypanosome tubulin and, with this information, produce new tubulin-binding compounds for assessment in vitro and in vivo. Upon completion of the project it is expected that drug binding sites on trypanosome tubulin will be characterised and at least one candidate for clinical trials identified.Read moreRead less
Electrophysiological and Anatomical Characterization of the Coronary Sinus Musculature and its Relationship to the Atria. This series of experiments will characterise the normal coronary sinus musculature and its connectivity to the atria of the heart and establish their electrical relationships. The underlying characteristics of the muscular connections will also be evaluated with a view to possible future manipulations of the system. Understanding normal heart impulse propagation is paramount ....Electrophysiological and Anatomical Characterization of the Coronary Sinus Musculature and its Relationship to the Atria. This series of experiments will characterise the normal coronary sinus musculature and its connectivity to the atria of the heart and establish their electrical relationships. The underlying characteristics of the muscular connections will also be evaluated with a view to possible future manipulations of the system. Understanding normal heart impulse propagation is paramount before we can understand and develop treatments for dealing with heart problems. This information will facilitate the development of techniques to treat and prevent heart rhythm disorders that are a common cause of morbidity in the community.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
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
New drugs for malaria that target histone deacetylases. There is no vaccine for malaria and current drugs are failing, contributing to millions of malaria-related deaths each year. The aim of this project is to develop new drugs to address this significant global health issue. This project will focus on drugs that act in novel ways to existing malaria drugs by targeting enzymes that are involved in altering gene expression in the parasite. These kinds of enzymes are recognised drug targets in ot ....New drugs for malaria that target histone deacetylases. There is no vaccine for malaria and current drugs are failing, contributing to millions of malaria-related deaths each year. The aim of this project is to develop new drugs to address this significant global health issue. This project will focus on drugs that act in novel ways to existing malaria drugs by targeting enzymes that are involved in altering gene expression in the parasite. These kinds of enzymes are recognised drug targets in other diseases such as cancer. The outcomes of this project will include advances in malaria drug development that build on Australian drug discovery efforts, seeding further funding opportunities from industry and other sources and contributing research training and capacity building in Australia.Read moreRead less
Molecular evolution and toxinology of colubrid snake venom toxins. This project proposes to examine the origin and evolution of venom systems in advanced snakes (Caenophidia) focusing on the colubrid radiation comprising the rear-fanged species. Demonstration by us of the presence of a potent postsynaptic neurotoxin in the Durvenoy's secretions of the Asian ratsnake Elaphe radiata, an archetypal non-venomous colubrid species, forced a fundamental rethink of venom evolution. The toxin is homologo ....Molecular evolution and toxinology of colubrid snake venom toxins. This project proposes to examine the origin and evolution of venom systems in advanced snakes (Caenophidia) focusing on the colubrid radiation comprising the rear-fanged species. Demonstration by us of the presence of a potent postsynaptic neurotoxin in the Durvenoy's secretions of the Asian ratsnake Elaphe radiata, an archetypal non-venomous colubrid species, forced a fundamental rethink of venom evolution. The toxin is homologous with the three finger toxins, previously thought unique to elapids, and supports the role of venom as a key evolutionary innovation in the diversification of advanced snakes. This project extends this work to other species and toxin families.Read moreRead less
Characterisation of two-pore domain potassium channels: structure-function studies of the M1-P1 loops of TASK channels. TWIK-related Acid Sensitive K+ (TASK) channels are members of the novel class of two-pore domain potassium channel family. They are potently inhibited by local anaesthetics and have been implicated as having important roles in many pathophysiological conditions such as heart arrythmias, stroke, epilepsy, breast and other cancers. The in depth structural and functional character ....Characterisation of two-pore domain potassium channels: structure-function studies of the M1-P1 loops of TASK channels. TWIK-related Acid Sensitive K+ (TASK) channels are members of the novel class of two-pore domain potassium channel family. They are potently inhibited by local anaesthetics and have been implicated as having important roles in many pathophysiological conditions such as heart arrythmias, stroke, epilepsy, breast and other cancers. The in depth structural and functional characterisation of this class of potassium channels is of great importance as they are interesting targets for new therapeutic developments. Advancement of knowledge in the structure and function of these channels will underpin drug targeting that will aid preventative healthcare, allowing Australians to age well and age productively.Read moreRead less
Regenerating lizard tails: A model for understanding the process of lymphangiogenesis. In humans, impaired lymphatic drainage in limbs causes the debilitating swelling termed lymphoedema. Lymphoedema affects 500,000,000 people worldwide. In the developed world lymphoedema predominantly results from surgery for cancer, and occurs in approximately 25% of breast cancer patients. We will examine lymph vessel regeneration (lymphangiogenesis) in a naturally regenerating, complex structure (the lizard ....Regenerating lizard tails: A model for understanding the process of lymphangiogenesis. In humans, impaired lymphatic drainage in limbs causes the debilitating swelling termed lymphoedema. Lymphoedema affects 500,000,000 people worldwide. In the developed world lymphoedema predominantly results from surgery for cancer, and occurs in approximately 25% of breast cancer patients. We will examine lymph vessel regeneration (lymphangiogenesis) in a naturally regenerating, complex structure (the lizard tail), to describe the regrowth process and determine the abundance, location, functional properties and molecular control of the new lymphatics. Furthermore, if reptilian lymphatic growth factors can promote lymphangiogenesis in mammals, we can design novel therapeutic approaches using reptilian ligands to promote lymphangiogenesis in lymphoedematous human tissues.Read moreRead less
Impact of shear stress on vascular adaptations in humans. Large arteries are important for the delivery of blood and oxygen to organs such as the heart and brain. A primary physiological stimulus which controls the size and function of these crucial arteries is the magnitude of flow or, more accurately, shear force that the inner wall of the artery is exposed to. We have developed novel software which enables non-invasive assessment of arterial wall velocity, diameter and blood flow. We will ass ....Impact of shear stress on vascular adaptations in humans. Large arteries are important for the delivery of blood and oxygen to organs such as the heart and brain. A primary physiological stimulus which controls the size and function of these crucial arteries is the magnitude of flow or, more accurately, shear force that the inner wall of the artery is exposed to. We have developed novel software which enables non-invasive assessment of arterial wall velocity, diameter and blood flow. We will assess the impact of acute and chronic changes in wall flow and shear on arterial size and function. We will also develop new software which measures other aspects of artery wall behaviour. These basic human physiology studies have direct implications for assessment of artery health in humans.Read moreRead less