Alzheimer’s disease (AD), is the most common form of dementia, accounting for between 50-70% of all cases. There is general agreement that current treatments for AD/dementia are inadequate so new treatment strategies are desperately needed. I am addressing these challenges by developing new technologies to generate next generation treatments for AD.
Enhancing The Cardioprotective Effect Of Diadenosine Tetraphosphate: Designing Inhibitors Against Ap4A Hydrolase
Funder
National Health and Medical Research Council
Funding Amount
$442,500.00
Summary
Ischemia describes the condition where blood flow in the blood vessels of the heart is decreased or blocked, preventing delivery of oxygen and nutrients to the heart. Ischemic preconditioning is a phenomenon where short bursts of ischemia, followed by reperfusion, actually protect the heart from a subsequent longer period of ischemia. The biochemical signalling events involved in preconditioning are complex and incompletely defined, but most likely involve multiple pathways, although the mitocho ....Ischemia describes the condition where blood flow in the blood vessels of the heart is decreased or blocked, preventing delivery of oxygen and nutrients to the heart. Ischemic preconditioning is a phenomenon where short bursts of ischemia, followed by reperfusion, actually protect the heart from a subsequent longer period of ischemia. The biochemical signalling events involved in preconditioning are complex and incompletely defined, but most likely involve multiple pathways, although the mitochondrial ATP-dependent potassium channel may be in common with most pathways. Pretreatment with the compound diadenosine tetraphosphate (Ap4A) mimics ischemic preconditioning with noticeable reductions in tissue necrosis (cell death). This treatment has been shown in experimental work to protect the heart during periods of stress such as in heart surgery or recovery from an ischemic event. The biological site of action by Ap4A may be the mitochondria ATP-dependent potassium channel or an associated protein. Ap4A can be degraded by enzymes located inside and on the outside of heart cells, notably by two forms of Ap4A hydrolase. We will use antibody assays to understand the specific localization and amount of Ap4A hydrolase before and after ischemia and after ischemic preconditioning in human heart muscle and blood vessels. We propose to determine the structure of the enzyme and use novel computer methods to screen databases for potential inhibitors. These inhibitors of Ap4A hydrolase activity could aid the design of a potent inhibitor that would prevent Ap4A hydrolase from degrading Ap4A and therefore enhance the cardioprotective properties of Ap4A as well as minimizing side effects from the break down of Ap4A. We will also use these inhibitors and other known non-degradable Ap4A analogues in bioassays to test the relative significance of Ap4A hydrolase present in different cellular locations.Read moreRead less
Function And Inhibition Of Plasmepsin V In Targeting Malaria Virulence Proteins Into Human Erythrocytes
Funder
National Health and Medical Research Council
Funding Amount
$407,845.00
Summary
Malaria parasites dramatically renovate infected erythrocytes to survive and evade the host immune system by delivering hundreds of exported parasite proteins into the cell. The parasite protease Plasmepsin V is essential for protein export. We aim to develop potent inhibitors of this protease in the hope of blocking its function and killing the parasite. We also aim to discover the components of the trafficking pathway after cleavage by Plasmepsin V that sorts virulence proteins to the host cel ....Malaria parasites dramatically renovate infected erythrocytes to survive and evade the host immune system by delivering hundreds of exported parasite proteins into the cell. The parasite protease Plasmepsin V is essential for protein export. We aim to develop potent inhibitors of this protease in the hope of blocking its function and killing the parasite. We also aim to discover the components of the trafficking pathway after cleavage by Plasmepsin V that sorts virulence proteins to the host cell.Read moreRead less
Many of the most serious diseases of Western societies including obesity, Type 2 diabetes, cancer growth and metastasis and cardiovascular disease have metabolic dimensions. The enzyme AMPK regulates cellular and whole body energy homeostasis by coordinating metabolic pathways to balance energy demand with nutrient supply. We are studying the structure and function of AMPK with the aim of better treating metabolic diseases.
Resolving And Targeting The Complex Molecular Mechanisms Underlying GPCR Signalling
Funder
National Health and Medical Research Council
Funding Amount
$1,071,370.00
Summary
Receptors are located on the surface of all human cells to allow our cells to respond to their environment. Over 30% of prescription drugs act through particular receptors called GPCRs, however effective drugs without side effects are difficult to develop because we do not have a deep understanding of how GPCRs transmit complex signals. In this proposal we seek to resolve the atomic-level details of GPCR signalling to assist in the development of better drugs for a diverse range of diseases.
Throughout our lives cells must die and be replenished. One way multicellular organisms remove unwanted cells is through a process called programmed cell death. This process eliminates redundant, damaged or infected cells by a program of cell suicide. We are studying the underlying molecular mechanisms of this cell suicide in order to design new pharmaceuticals to treat illnesses caused by a disruption in programmed cell death. The fine balance between living and dying cells must be maintained a ....Throughout our lives cells must die and be replenished. One way multicellular organisms remove unwanted cells is through a process called programmed cell death. This process eliminates redundant, damaged or infected cells by a program of cell suicide. We are studying the underlying molecular mechanisms of this cell suicide in order to design new pharmaceuticals to treat illnesses caused by a disruption in programmed cell death. The fine balance between living and dying cells must be maintained and if this balance is lost then disease may result. A reduced level of cell death may result in cancers while too many dying can contribute to degenerative diseases such as Alzheimer's disease and stroke. Currently many of these diseases do not have effective treatments. We will determine the three-dimensional structures of key proteins involved in programmed cell death and use this information to design drugs that can interfere with the molecular processes involved in signalling cell death. Such drugs may prove useful new therapies in a wide range of diseases caused by a breakdown in the biochemical paths to cell death.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE240100161
Funder
Australian Research Council
Funding Amount
$407,598.00
Summary
Translational Design: Product Development for Research Commercialisation. Australia is a world leader in fundamental research. Yet, ranks as one of the worst developed nations for translating research into new-to-market innovation. This project explores a new role for design as a critical component of research commercialisation and innovation ecosystems. It expects to contribute novel insights into how designers can be better integrated into interdisciplinary research directed towards commercial ....Translational Design: Product Development for Research Commercialisation. Australia is a world leader in fundamental research. Yet, ranks as one of the worst developed nations for translating research into new-to-market innovation. This project explores a new role for design as a critical component of research commercialisation and innovation ecosystems. It expects to contribute novel insights into how designers can be better integrated into interdisciplinary research directed towards commercial outcomes. Expected outcomes include a framework and toolkit for a paradigm-shifting design approach to translating fundamental research into products commercialised and manufactured in Australia. This should provide enhanced economic benefit, building Australia’s sovereign capability in new-to-market innovation.Read moreRead less
Designing for wellbeing: realizing benefits for patients through best practice hospital design. The environmental design of healthcare facilities has been shown to directly affect the wellbeing of patients and their families. Poorly designed environments exacerbate patient anxiety and stress and diminish their healthcare experience. Environments designed to support a patient’s wellbeing result in improved health outcomes. Building upon Australia’s international leadership in contemporary hospita ....Designing for wellbeing: realizing benefits for patients through best practice hospital design. The environmental design of healthcare facilities has been shown to directly affect the wellbeing of patients and their families. Poorly designed environments exacerbate patient anxiety and stress and diminish their healthcare experience. Environments designed to support a patient’s wellbeing result in improved health outcomes. Building upon Australia’s international leadership in contemporary hospital design, this project aims to evaluate, prioritise and strategise the best means for realising benefits of environmental design factors that contribute most significantly to achieving positive outcomes for patients and families. It aims to achieve this through a comprehensive comparative case study analysis of new Australian paediatric hospitals.Read moreRead less
Digital fabrication technologies: analysing patterns of adoption and innovative transformations in architectural design and practice. This project on adoption of digital fabrication technologies by Australian architecture practices will reveal emerging opportunities for creative design and associated transformations in the design practices. These outcomes will enable the increasingly globalising sector of architectural design services to become more agile and innovative.
Place and parametricism: Provocations for the rethinking of design. This project aims to explore whether quantitative methods of digital and parametric design can adequately encompass place. Quantitative digital and parametric approaches increasingly dominate contemporary architecture, but people assume architectural design should be essentially oriented to questions of place. The project will operate through a set of studio provocations based on the fictional places of Mervyn Peake's Gormenghas ....Place and parametricism: Provocations for the rethinking of design. This project aims to explore whether quantitative methods of digital and parametric design can adequately encompass place. Quantitative digital and parametric approaches increasingly dominate contemporary architecture, but people assume architectural design should be essentially oriented to questions of place. The project will operate through a set of studio provocations based on the fictional places of Mervyn Peake's Gormenghast novels. The project is expected to clarify the nature of place and parametricism, and rethink what design itself might be.Read moreRead less