Protein-protein interactions mediate most biological processes and are therefore important therapeutic targets. The biological activity of a protein usually stems from only a small localised region on its surface. At the molecular level such regions often correspond to key secondary structures known as alpha-helices or beta-sheets that reside within the protein. Creating molecules able to mimic these regions while retaining their structure are attractive options for drug design. However short regions of a protein are usually unable to adopt these structures in the absence of the rest of the protein. Rather, they populate random structures that are susceptible to degradation in addition to other shortcomings such as their inability to cross biological membranes and poor bioavailability. To circumvent these issues we will collaborate with the Fairlie, a world leader in secondary structure mimetics, to create peptides that are able to form bioactive alpha-helices and beta-sheets in isolation. This will be achieved by introducing helix- or strand-inducing tethers into our growing collection of library derived peptides. Shorter constrained peptides can be derived from larger peptides known to bind with high affinity to their target. Our efforts will focus on two key areas in which we have track record: i) creating peptides to antagonise the oncogenic transcriptional regulator, Activator Protein-1. We have previously used library screening assays to derive a range of peptides capable of antagonising function. We have already worked with Fairlie to demonstrate feasibility for this approach by targeting one AP-1 partner known as cFos and shedding over 40% of the peptide in the process. Using this approach we were able to derive stable helix-constrained peptides specific for their target protein that also resisted degradation (Rao et al, PLOS One 2013). We believe that much high affinity interactions can be achieved by targeting another AP-1 component, known as cJun, where many more hydrophobic interactions required for high binding affinity can be formed. Previous related work has demonstrated that this approach can yield tethered peptides as short as five amino acids (Harrison et al, PNAS, 2010) that are able to meet many of the requirements necessary for a drug, such as high stability and resistance to biological breakdown. ii) Creating peptides capable of modulating amyloid formation. We have used library screening to derive small beta-strand peptides that bind to the Alzheimer's beta-amyloid peptide (Acerra et al, Protein Eng Des Sel 2013). We now seek to collaborate with Fairlie in creating mimetics of these short peptides that result in improved compounds that are able to circumvent many of the above issues. To achieve these goals Mason will travel to the Institute for Molecule Bioscience (IMB) at the University of Queenland on three visits over three years to further develop our collaboration with the Fairlie group. Fairlie is internationally known as a research and opinion leader in chemistry, biochemistry, pharmacology, and drug discovery. The award will permit Mason to gain new skills and techniques that can be brought back to Essex and further developed in the UK, in addition to the exchange of ideas and the further development of the collaboration. Having developed methods for stabilising alpha-helices and beta-strands in general there will be considerable scope to apply these techniques, and consequent rules for peptide and peptide mimetic design, to other peptide systems. Finally while at Queensland there will also be ample opportunity to hold seminars and meet and discuss research plans with other members of the IMB (e.g. Professors Glenn King and David Craik) who have similar interests in developing peptide-based drugs.

Brigalow forest communities, are dominated by an acacia tree, Acacia harpophylla (brigalow), and once occupied ~8 M ha across the Brigalow Belt region of northeastern Australia in Queensland, but have been reduced to 8% of their former range through clearing for conversion of the land to pasture. Brigalow forests are only found in this region of the world and support a unique flora and fauna which as an ecological community is now listed as endangered under the Australian Environmental Protection and Biodiversity Conservation Act (EPBC). The recovery plan for Brigalow ecological communities identifies lack of knowledge on the ecology of brigalow as a threat to their recovery and recommends that further research on brigalow and how to restore degraded forests should be carried out. In the proposed research, we will advance the knowledge on the ecology of Brigalow. In particular we will provide empirical evidence that will further our understanding of how brigalow respond to habitat disturbance caused by human activities. Specifically, we will compare dispersal by seed (sexual reproduction) and dispersal by root suckering (clonal reproduction) in remnant and disturbed secondary brigalow (regrowth) forests using genetic markers. This is a unique opportunity to find out about the reproductive biology of the species because brigalow only produces seeds very rarely. Such a rare seed recruitment event occurred early in 2008, for the first time in 60 years, and seedlings established in both remnant and regrowth brigalow. We expect to find that the genetic diversity in adults and seedlings of regrowth brigalow is lower than in remnant brigalow because of extensive root suckering in regrowth Brigalow. Indeed, in regrowth, it is expected that dispersal occurs primarily by clonal reproduction because it allows the species to rapidly colonise open land, but it has never actually been assessed. The lack of genetic diversity in regrowth Brigalow may ultimately have detrimental genetic effects for its viability because genetic diversity enables a species to respond and adapt to change in environmental conditions. One way to help maintain genetic diversity in regrowth Brigalow is to design active management strategies that optimize genetic diversity, for instance by removing suckers (thinning). As we will record the spatial location of trees and seedlings, as well as identify their genetic identity, we will be able to produce a geographic map of the location of clones and the distance of dispersal of seeds and we will be able to use this information in a model to predict which thinning management strategy best optimises genetic diversity in restored brigalow stands, as well as restore forest structure and carbon sequestration (which is how much carbon is stored in the trees) to the levels of mature remnant forests. This has economic implications for carbon markets and mined-land rehabilitation.The proposed research will considerably advance our knowledge of the biology of brigalow acacia in its natural environment, and will contribute to fill the gap of knowledge identified by the EPBC on how to successfully restore degraded Brigalow communities. We will make practical recommendations to inform sustainable restoration management of Brigalow forests. Generally, the project will further our understanding of how tree species respond to habitat disturbance, especially for partially clonal species for which no empirical data are available. This is important because degraded regrowth forests are now predominant worldwide, and we need to understand how tree species respond to widespread disturbance as a result of human activities in order to carry out economic activities in an environmentally sustainable way. Finally, this project will present a genetic model of thinning management, which is novel in restoration ecology. The approach, when adopted elsewhere, will improve the long-term sustainability of ecological restoration programmes.

Transducers are devices that can convert electrical energy into mechanical energy and vice versa. They are widely used in non-destructive testing to generate acoustic signals in test materials and to detect changes in the acoustic signal as it travels enabling material properties to be determined. The application areas for transducers in non-destructive testing are diverse and range from locating cracks in metal structures to diagnosing disease in humans. Transducers are typically made from single crystals such as quartz or ceramics. Recently it has been shown that a much wider range of materials can be used in transducers if they are miniaturised down to a nanometre scale. In fact, it has been shown that electrical energy can be converted to mechanical energy in biological membranes. Further, strategies to greatly increase the size of this effect have also been identified. These findings are very exciting as they pave the way for development of tiny transducers that could be used in the human body without posing any risk of toxicity, thus having tremendous potential for application in medicine. The work proposed in this Fellowship is centred on the development of nano-sized transducers made from phospholipids, which are the main type of fat found in membrane of biological cells. A huge area of application for the nano-transducers proposed is in medical imaging which presents a number of challenges. In practice, the nano-transducers could be used to remotely probe tissue properties and used in an imaging system to aid the diagnosis of disease. There is also a growing need for new imaging systems capable of remotely studying cells and tissues in the body to support the development of emerging therapies that use human cells to treat currently incurable conditions, such as Parkinson's disease and spinal injury, as well as chronic conditions including diabetes and heart disease. The hope is that by introducing new healthy cells into the body they will help to restore the function of injured or diseased cells. To ensure these therapies have a positive effect it is important that the location and behaviour of introduced cells are tracked once in the body. This is a challenging problem which current technologies are struggling to address. The work proposed in this Fellowship will address the above challenges. The approach that will be taken is different from other workers particularly as it will involve the development of transducers made from organic material. A major part of the proposed work will be designing and fabricating the nano-transducers. The phospholipids the nano-transducers will be composed of will be formed into bubbles called liposomes. Due to the natural link between the electrical and mechanical properties of liposomes it will be possible to use them as tiny acoustic sources. Strategies to increase the size of the acoustic signal produced will be developed based on modification of the liposome composition, shape and size. Another part of this Fellowship will be the development of a suitable imaging system using the nano-transducers that can be used to produce diagnostic images of the body. Also by controllably decorating the liposomes with specific biological molecules the nano-transducers will be able to target certain cell types enabling them to act as beacons to locate cells in the body. The final part of the work will be centred on demonstrating the capability of the new imaging system using tissue phantoms that mimic the human body. In particular, the ability to detect tumours, electrical activity in the brain and track cells used in therapy will be investigated. Overall, the success of this work will deliver a new medical imaging modality that could be implemented readily within clinical pathways at the point of care. This would have a significant impact on healthcare and enable new therapies to become available for clinical use and thus contribute to the health and wealth of society.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Protein-protein interactions mediate most biological processes and are therefore important therapeutic targets. The biological activity of a protein usually stems from only a small localised region on its surface. At the molecular level such regions often correspond to key secondary structures known as alpha-helices or beta-sheets that reside within the protein. Creating molecules able to mimic these regions while retaining their structure are attractive options for drug design. However short regions of a protein are usually unable to adopt these structures in the absence of the rest of the protein. Rather, they populate random structures that are susceptible to degradation in addition to other shortcomings such as their inability to cross biological membranes and poor bioavailability. To circumvent these issues we will collaborate with the Fairlie, a world leader in secondary structure mimetics, to create peptides that are able to form bioactive alpha-helices and beta-sheets in isolation. This will be achieved by introducing helix- or strand-inducing tethers into our growing collection of library derived peptides. Shorter constrained peptides can be derived from larger peptides known to bind with high affinity to their target. Our efforts will focus on two key areas in which we have track record: i) creating peptides to antagonise the oncogenic transcriptional regulator, Activator Protein-1. We have previously used library screening assays to derive a range of peptides capable of antagonising function. We have already worked with Fairlie to demonstrate feasibility for this approach by targeting one AP-1 partner known as cFos and shedding over 40% of the peptide in the process. Using this approach we were able to derive stable helix-constrained peptides specific for their target protein that also resisted degradation (Rao et al, PLOS One 2013). We believe that much high affinity interactions can be achieved by targeting another AP-1 component, known as cJun, where many more hydrophobic interactions required for high binding affinity can be formed. Previous related work has demonstrated that this approach can yield tethered peptides as short as five amino acids (Harrison et al, PNAS, 2010) that are able to meet many of the requirements necessary for a drug, such as high stability and resistance to biological breakdown. ii) Creating peptides capable of modulating amyloid formation. We have used library screening to derive small beta-strand peptides that bind to the Alzheimer's beta-amyloid peptide (Acerra et al, Protein Eng Des Sel 2013). We now seek to collaborate with Fairlie in creating mimetics of these short peptides that result in improved compounds that are able to circumvent many of the above issues. To achieve these goals Mason will travel to the Institute for Molecule Bioscience (IMB) at the University of Queenland on three visits over three years to further develop our collaboration with the Fairlie group. Fairlie is internationally known as a research and opinion leader in chemistry, biochemistry, pharmacology, and drug discovery. The award will permit Mason to gain new skills and techniques that can be brought back to Essex and further developed in the UK, in addition to the exchange of ideas and the further development of the collaboration. Having developed methods for stabilising alpha-helices and beta-strands in general there will be considerable scope to apply these techniques, and consequent rules for peptide and peptide mimetic design, to other peptide systems. Finally while at Queensland there will also be ample opportunity to hold seminars and meet and discuss research plans with other members of the IMB (e.g. Professors Glenn King and David Craik) who have similar interests in developing peptide-based drugs.