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Marsden fund success for 2018

3:14pm

Successful standard Marsden grant proposals

Professor Hallie Buckley, Anatomy - Principal investigator
Peter Petchey, Anthropology and Archaeology - Co-Principal investigator

The Best of Times, the Worst of Times: A Biocultural investigation of 19th century frontier mining cemeteries in Australia, New Zealand and California
$827,000

Thousands of people left the Old World in the 19th century to take part in the gold rushes in California USA, Victoria, Australia and Otago, New Zealand. While early rush participants were often of European descent, other ethnicities participated, especially the Chinese. It was both the best of times and the worst of times, with the promise of easy wealth but the risk of sickness or violent death. Although historical records document the hardships of mining life, they are often silent on roles played by women, children, and the disenfranchised.

Archaeology is often the sole avenue of enquiry for these “voices”, but here too there are gaps. Goldfields archaeology is extensive, however, the distinct cultural identity of individuals is often masked by a common material culture and health is rarely examined. Bioarchaeology, the analysis of archaeological human skeletal remains, adds to the historical narrative through direct biological evidence. Historic cemeteries provide a wealth of biological and cultural information, illuminating the lives of people during this time.

We will explore adaptations to mining life in all these Pacific Rim regions by analysing the mortuary ritual of the communities, quality of life of the people, and the landscapes in which they lived.

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Associate Professor Stephen Bunn, Anatomy - Principal investigator

Monitoring and manipulating neuronal activity in the maternal brain during lactation
$911,000

This proposal will challenge, and potentially overturn, our long-held understanding of the mechanism controlling prolactin secretion from the pituitary. Elevated prolactin levels are critical for lactation but mechanisms responsible for its secretion at this time are poorly understood. In non-lactating mammals, prolactin secretion is held in check by a negative feedback pathway mediated by prolactin-sensing hypothalamic dopaminergic neurons. It is currently believed that during lactation these neurons become insensitive to prolactin thus interrupting the negative feedback pathway and allowing prolactin levels to rise.

We have published new evidence that this model is unlikely to be correct in that electrophysiological studies show that these neurons remain prolactin responsive during lactation. Surprisingly, however, they appear to undergo a lactation-associated change in phenotype and switch from releasing dopamine to releasing the opioid peptide enkephalin.

Thus, we propose that contrary to becoming silent during lactation these neurons actually take on a new, but yet to be defined, role.

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Professor John Reynolds, Anatomy - Principal investigator and
Dr Louise Parr-Brownlie, Anatomy - Co-Principal investigator

Beauty vs the Beast: How does our brain prepare us to respond appropriately to beauty or fear?
$959,000

Classical conditioning, as demonstrated by Pavlov, is the process whereby a neutral stimulus that repeatedly precedes delivery of a reward begins to elicit behaviour. Intriguingly, by a mechanism as yet unknown, our perception in sensory areas adapts during conditioning to maximise detection of stimuli associated with rewarding outcomes.

We hypothesise that changes in primary sensory areas occur in response to neutral stimuli that predict the arrival of both reward and punishment, but are driven by different neuromodulator systems. Here we will measure the response in the superior colliculus to visual stimuli predicting both reward and punishment, and use pharmacology and optogenetics to determine the cellular mechanisms underlying changes in sensory responsiveness. We will also measure the effect of altered sensory responsiveness in the basal ganglia, where sensory inputs are thought to be incorporated into the generation of behaviour.

This work will increase our knowledge of how the perception of sensory information associated with behaviourally relevant outcomes is heightened and leads to the selection of particular behavioural reactions. It holds the potential of providing new therapeutic targets for disorders such as post-traumatic stress disorder, anxiety, or addiction, where heightened responsivity in primary sensory regions may trigger debilitating behaviours.

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Dr Tania Slatter, Pathology, Dunedin School of Medicine - Principal investigator

The Δ133p53 path to cancer: a new role for the Δ133p53 p53 isoform in cell surface trafficking
$786,000

P53 is a gene that helps to suppress cancer. However, a p53 variant, Δ133p53, has an opposing effect: it promotes cancer. We have learned that Δ133p53 is increased in aggressive cancers and that it has several properties that promote tumour growth and invasion. We propose that Δ133p53 promotes multiple aspects of cancer through a central mechanism that increases cell surface protein trafficking. If our hypothesis is correct, a new core mechanism will explain how Δ133p53 facilitates cancer development.

We will test our hypothesis using three goals: 1) To establish that Δ133p53 increases trafficking of proteins to the cell surface; 2) To determine how Δ133p53 mediates increased cell surface trafficking; and 3) To determine if stopping Δ133p53 mediated cell surface trafficking reduces cancer.

Understanding how cancer promoting signals are recruited to the Δ133p53 cell surface, identifying the mechanism by which Δ133p53 increases cell surface signalling and how this can be inhibited can provide new opportunities to treat Δ133p53-expressing tumours.

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Associate Professor Sian Halcrow, Anatomy - Principal investigator

Small beginnings, significant outcomes: A new life-course approach to understanding the impacts of social inequality on human health in ancient China
$826,000

Social inequality is the hallmark for state-level societies worldwide, which has significant repercussions for nearly half the world’s population who now live in poverty, affecting women and children most severely. To understand health disparities today, we need to study how inequality developed and how it impacted people in the past. The fertile Yellow River valley, known as the “cradle of Chinese civilisation", witnessed the development of one of the most durable states in the world.

Recent research in this region has shown a deterioration in health and diet for women in the Bronze Age compared with the preceding Neolithic period. To fully understand this change, we will assess health and diet in large skeletal samples that cover socio-political development from the early agricultural societies to the stratified Han Dynasty. Using new methods to uncover childhood gender and diet, we will develop an original model to explain the development of diet and health inequality over the life course during five millennia of profound social change.

This research is the first New Zealand-run bioarchaeological project in China and will place us at the forefront of methodological and theoretical development in the field.

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Dr Peter Mace, Biochemistry - Principal investigator

Inflammation or death via the ASK signalosome – why not both?
$958,000

How does the body judiciously respond to challenges when the immune system is already on alert? Metabolic imbalances during obesity and diabetes chronically challenge the immune system, and further stressors that may be relatively benign can cause serious inflammatory disease. In response to metabolic or microbial stress, apoptosis signal-regulating kinases (ASKs) form large multiprotein complexes that promote cellular responses such as cell death and/or inflammation. Humans have three different ASK proteins, which can function alone or together. The molecular mechanisms that allow ASK proteins to drive responses ranging from minimal (inflammation) to extreme (cell death) are unclear.

In this project, we seek to understand how ASK proteins assemble into macromolecular signalling hubs. We will capture three-dimensional structures that show how multiple ASK proteins work together; and use novel biochemical tools to investigate why complexes with mixtures of different ASK proteins cause more extreme cellular responses. The confluence of metabolic imbalance and microbes is a major frontier in human health, which converges in disrupted cellular stress response pathways.

Understanding how ASK proteins function alone, and together, in light of chronic and acute stressors is a major piece of this puzzle, and integral to both normal homeostasis and inflammatory disease.

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Dr Laura Gumy, Anatomy - Principal investigator

Mechanisms regulating long-range intracellular transport in neurons
$938,000

Axons are the long protrusions of neurons that transmit information to other nerve cells and tissues. Long-distance transport of molecules within the axon is critical for neuronal function. Transport involves the movement of proteins, RNAs, lipids and organelles, by motor proteins that move along cytoskeletal microtubules. Despite the critical importance of long-range transport to proper neuronal functioning, the mechanisms regulating the distribution of cargoes in axons over long distances are poorly understood. Recently, we uncovered that microtubule associated proteins control motor-based transport in neurons.

Given the ubiquitous presence of many microtubule associated proteins in axons, we hypothesise the existence of a “MAP code” where microtubule associated proteins provide signals to coordinate specific transport routes. To test our hypothesis we will use state-of-the-art high-resolution live-imaging microscopy techniques to create dynamic maps of molecule movement within full-length axons. Combined with biochemical and optogenetic assays we will identify how specific microtubule associated proteins regulate the activity of various motor proteins to direct transport.

In addition to deciphering the fundamental mechanisms of long-range transport processes in neurons, our work has the potential to contribute to the discovery of new therapeutic targets for treatment of diseases associated with intracellular trafficking defects.

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Professor Christine Winterbourn, Pathology (University of Otago, Christchurch) - Principal investigator

Characterising the role of a newly identified peroxidase in melanoma
$915,000

Peroxidasin is a recently identified but poorly characterised mammalian peroxidase enzyme. It is essential for the formation of connective tissue throughout the body and interestingly, is highly upregulated in metastatic melanoma cells with an invasive phenotype. Nothing is known about its function in melanoma. Evidence suggests that its role in connective tissue formation could be important, but it could act in other so far unidentified ways. Peroxidasin converts bromide ions to hypobromous acid, a reactive chemical similar to household bleach. In connective tissue, it forms an unusual chemical bond in collagen IV.

However, hypobromous acid can react with many biological targets, and peroxidasin has other peroxidase activities that may contribute to its physiological function. We propose to study the biochemistry and cell biology of peroxidasin in metastatic melanoma cell lines. We will establish how its peroxidase activity modifies cell constituents and whether its activity contributes to the invasive characteristics of high expressing cells. Peroxidasin inhibitors will be tested for their ability to limit cell invasion.

Our study will advance understanding of peroxidasin function and test the relevance of a novel mechanism of tumour cell invasion. Positive findings would support exploration of peroxidasin as a therapeutic target in metastatic melanoma.

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Associate Professor Alexander McLellan, Microbiology and Immunology - Principal investigator

Tuneable activation of anti-cancer T cells using auto-inducible promoters
$960,000

T-cell-based immunotherapy has shown great success for the treatment of haematological cancers – with emerging potential for the treatment of solid cancers. However, successful chimeric antigen receptor (CAR) T cell therapy is limited by both the low persistence of CAR T cells, as well as the low differentiation rate into memory T cells. In lymphoma patients treated with anti-CD19 CAR T cells, clinical responses are associated with rapid CAR T cell expansion. To improve control of T cell expansion, we will utilise an auto-inducible promoter to enhance CAR T cell survival and memory responses.

The design will allow pro-survival genes to be selectively and transiently switched on in T cells in contact with cancer-associated antigens. This will not only boost in vitro expansion, but will also enhance the activity of adoptively transferred antigen-specific CAR T cells in the patient. Our strategies are designed to result in minimal perturbations to the genetic structure of CAR T cell constructs.

However, these original approaches will greatly improve the utility of CAR T cells for the treatment of both leukaemias and solid tumours.

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Dr Timothy Hore, Anatomy - Principal investigator

Epigenetic sex determination and inheritance
$854,000

The germ germline encodes all of the biological information to be passed to the next generation. While much of this information is genetic and therefore encoded in DNA sequence, it is becoming increasingly clear that non-genetic, or “epigenetic” traits can also be inherited. Inheritance of these traits is rare in mammals due to erasure of epigenetic information in the germline. However, using zebrafish as a model, we have discovered that germline epigenetic erasure is not obligatory. We plan to use targeted epigenetic editing to test if removal of germline erasure allows broad-scale transmission of epigenetic information, and we will uncover the effect this has on inheritance and subsequent development. Of these subsequent developmental processes, perhaps the most distinctive is sex determination.

We have found that female differentiation in zebrafish is inextricably linked to the expansion of DNA encoding specialised cellular machines that make protein, and is likely controlled by epigenetic modification. We will define how epigenetic modification impacts upon this specialised machinery and sex determination, and further test the exciting possibility that this epigenetic determinant can be inherited, akin to a classical sex determining gene.

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Professor Michelle Glass, Pharmacology and Toxicology - Principal investigator

Applying human drug discovery approaches to kauri die back
$939,000

Phytophthora agathidicida is currently threatening New Zealand’s most iconic tree, the kauri. Current efforts to halt its spread through New Zealand forests are failing. Phytophtora zoospores swim through waterlogged soil towards the roots of their host plants and then encyst on the root surface and initiate infection. The molecular mechanisms controlling movement and infection appear to involve G protein coupled receptors and phospholipid kinases. This is exciting, as powerful methods are available for studying these proteins; indeed G protein coupled receptors and kinase together are the target of approximately 60 per cent of all current human medicines.

Here our multidisciplinary, international team propose a novel way to tackle the problem: by adapting methods refined in human drug discovery to understand the fundamental function of these proteins. This knowledge will enable us to develop novel chemical tools that could help in the fight against this devastating pest.

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Professor Catherine Day, Biochemistry - Principal investigator

Generating complexity in the ubiquitin code
$935,000

Attachment of ubiquitin to proteins is a pervasive post-translational modification that encodes information, which determines the logic of biological circuits and ultimately the phenotype of eukaryotic cells. The nature of the code relies on the choice and activity of the E2 and E3 enzymes – the writers of the ubiquitin code. As expected for such a critical process, dysregulation of ubiquitin-mediated events manifests as diseases such as cancer.

Recent studies by the researchers and others indicate that ubiquitin is not only a substrate of the E2/E3 writers, but also an important regulator of the writers. In this project, using biochemical approaches and novel tools, we will (i) determine how ubiquitin regulates the activity of the E2/E3 ubiquitin writers, and (ii) identify features that promote the addition of multiple ubiquitin molecules to substrates. The fate of each ubiquitylated protein is determined by the length and linkage-type of the attached chains.

Here we will reveal the mechanisms that promote the preferential modification of substrate proteins with multiple ubiquitin molecules. Disruption of the ubiquitin code is associated with a range of diseases that are the focus of drug discovery initiatives, and a detailed mechanistic understanding is central to the development of improved therapeutics.

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Fast-Start proposals (for early career researchers)

Dr Khoon Lim, Orthopaedic Surgery and Musculoskeletal Medicine (University of Otago, Christchurch) - Principal investigator

Harnessing macromolecular chemistry to mimic vascular developmental biology
Mentor: Associate Professor Tim Woodfield
$300,000

Functional vasculature is necessary to transport oxygen and nutrients to the tissues, and is the key to survival of almost all organs in the human body. Disruptions in the blood vessels or blood supply lead to a number of large scale clinical pathological diseases. To date, there are no treatments in the clinic allowing restoration of blood vessels to treat ischaemic tissues due to the incapability to accurately recapitulate the vascular architecture. 3D bioprinting which enables spatial localisation of biological cues and cells, has emerged as a potential solution.

We aim to develop a novel vascular bioink, capable of 3D bioprinting high resolution large constructs, with the appropriate soft mechanics required to facilitate functional vasculature formation. We believe that by harnessing macromolecular chemistry (visible light photo-initiating system, photo-click thiol-ene chemistry and di-tyrosine crosslinking) and advanced 3D printing technology, we will be able to synergistically provide both physical and biological cues required to engineer functional vascular networks.

The successful outcome of this project will allow restoration of blood macro- and micro-circulation in large ischaemic tissue, alleviating the current socio-economic burden of diseases such as ischaemic stroke, cardiovascular diseases and diabetic ulcers.

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Dr Sarah McKenzie, Dean’s Department (University of Otago, Wellington) - Principal investigator

Through the eyes of men: Towards a critical understanding of men’s mental health
Mentor: Professor Sunny Collings
$300,000

Every year the coroner releases New Zealand’s annual suicide statistics, and every year the media reminds us of this shameful “silent epidemic”. Yet we still do not understand why suicide is such an entrenched problem in this country. Perplexingly, we are no closer to understanding why men are three times more likely than women to take their own lives, or why young men in their early twenties have the highest rates of suicide of any age group.

This multidisciplinary study will provide the first in-depth gender analysis of how dominant ideas about ‘how to be a man’ in New Zealand society impact on young men’s mental health, leaving some at far greater risk of taking their own lives. Informed by critical gender theory and mental health geography, this project uses visual methods to enable men to document their experiences of living with depression, anxiety and suicidality.

The rich gender analysis of images and stories will provide original insights into how young men’s mental health-related beliefs and behaviours are influenced by masculinity, as well as how particular gendered places may help or hinder the ways in which men cope when going through crisis.

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Dr Rebecca Kinaston, Anatomy - Principal investigator

Waves of change: Human migration and adaptation in prehistoric Indonesia
Mentor: Dr Michael Knapp
$300,000

Prehistoric human migration and adaptation were key drivers of genetic and cultural evolution. In Island Southeast Asia (ISEA) and the Pacific, Indonesia played a central role in the prehistoric settlement of the region during two major time periods of human dispersal: the arrival of anatomically modern humans during the Pleistocene (possibly beginning ca 73,000 years before present- BP) and sea-faring, pottery making, Austronesian speakers during the mid-Holocene (ca. 5500-3000 BP).

For this project, we will excavate two newly-discovered Indonesian sites with exceptionally well-preserved human remains dating to these periods. We will use ancient DNA analysis to determine the genetic makeup of the prehistoric populations and assess patterns of human dispersal and interaction. Chemical analyses of bone (bulk and compound-specific stable isotope analyses) will be used to determine the diet of the people who lived at these sites and allow us to understand how humans adapted to their environments to obtain food.

Our findings will help unlock the mysteries of how humans migrated to and lived in the changing climatic and cultural landscape of Indonesia in the past. This research has the potential to significantly transform our knowledge of prehistoric human origins, dispersals and dietary adaptations in the Asia-Pacific region.

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Dr Matthew McNeil, Microbiology and Immunology - Principal investigator
Mentor: Prof Greg Cook

Exploiting the biological costs of drug resistance to design new therapeutic regimens against Mycobacterium tuberculosis
$300,000

Tuberculosis is now the leading cause of death by a single infectious agent worldwide. Infections with Mycobacterium tuberculosis are treatable, requiring a six-month combination therapy. However, drug resistance has rendered many of these antibiotics ineffective. New antibiotics represent lifelines in the fight against M. tuberculosis but without rationally designed combination therapies the development of resistance is inevitable. Drug resistance in M. tuberculosis occurs via chromosomal mutations that often incur a biological cost. Resistance against a single class of antibiotics can also render microbial cells hyper-sensitive or resistant to unrelated classes of antibiotics via a phenomenon termed collateral sensitivity.

Using a combination of microbiological and genetic approaches this research will identify resistance mechanisms that sensitize M. tuberculosis to alternative clinically relevant drug classes. Antibiotics with overlapping collateral pathways will be tested for an ability to prevent the emergence of resistance and to rapidly kill drug resistant strains.

This research has the potential to identify novel antibiotic combinations that can prevent the emergence of resistance and also shorten the duration of treatment. It is anticipated that these methodologies and results will be applicable to other bacterial pathogens where antimicrobial resistance is an emerging problem.

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Dr Soledad (Maria) Perez-Santangelo, Biochemistry - Principal investigator
Mentor: Associate Professor Richard Macknight

Adjusting the clock: How naturally occurring variation in circadian clock genes maximises plant growth and fitness in different environments
$300,000

Climate change is predicted to affect crop yield by reducing suitable agricultural land worldwide. Understanding the genetic basis of local adaptation is fundamental to developing crops suited to growing in the new environments that arises as a result of climate change. Legume crops are of particular concern as they are an essential source of protein for both humans and livestock.

This project will study the genetic basis of local adaptation in the model legume Medicago truncatula, by discovering the naturally occurring genetic variations in the master regulator of plant physiology - the circadian clock, and understand how these variations enhance their fitness to grow in their local regions. For this, we will 1) identify natural variation of clock function, 2) use genome-wide approaches to discover the genetic changes responsible for the variability of the clock, 3) study how these genetic variations enable plants to adapt to different geographical locations.

This knowledge will help develop more efficient plant breeding strategies by providing new targets for generating varieties specifically tailored for local regions and conditions. Such approaches are needed with climate change altering the geographical range where crop plants can be grown.

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Dr Michael Garratt, Anatomy - Principal investigator

Sensory control of life history and ageing in mice
$300,000

Life history theory is built on the assumption that there are trade-offs between life-history traits, such as between early and late-life reproduction, and between reproduction and lifespan. How these trade-offs are mediated is poorly understood. We hypothesize that sensory detection of social cues is an important regulator of life histories, providing the stimulus that promotes reproductive processes, but also self-imposing costs that reduce lifespan.

This project will use established mouse models to elucidate the role of olfaction – the dominant sense in most mammals – in control of reproductive life history and ageing. We will expose mice to either opposite-sex odours, indirect access to mates, or direct mating and test whether sensory cues are capable of stimulating life-history transitions and metabolic costs associated with reproduction. We will further utilise genetic models of impaired olfaction to define the role of specific olfactory systems in matching life-history responses to different social environments. Ultimately, we will test whether either olfactory stimuli, or sensory deficits, are sufficient to influence mouse lifespan and link early life reproduction to reproductive ageing.

This research could provide a new framework for understanding life-history trade-offs and reproductive plasticity, operating via sensory perception of the external environment.

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Dr Simon Jackson, Microbiology and Immunology
Mentor: Associate Professor Peter Fineran

Mobile CRISPR-Cas systems and the genesis of hybrid adaptive immunity in bacteria
$300,000

Bacteria are constantly threatened with infection by viruses. To protect themselves, many bacteria use an adaptive immune response mediated by CRISPR-Cas systems. CRISPR-Cas immune systems target and destroy the DNA or RNA of infecting viruses, thereby clearing the infection. All CRISPR-Cas systems evolved from a common origin, but they have diverged into many distinct types with different functions. It has been discovered that the genes encoding some CRISPR-Cas systems are mobile and can fuse with other CRISPR-Cas types to from hybrid immune systems. These hybrids are not considered in current models of CRISPR-Cas evolution.

This research will determine how these immune systems function compared to non-hybrid systems. There are also downsides to adaptive immunity provided by CRISPR-Cas systems, such as autoimmunity, and it will be determined whether hybrid CRISPR-Cas systems are less prone to these side effects than non-hybrid systems. We will also address how mobile CRISPR-Cas systems are acquired and fuse with existing CRISPR-Cas systems, giving rise to hybrid immune systems.

Overall, this research will provide insight into how and why hybrid CRISPR-Cas systems form and the implications of their occurrence for the coevolution of bacteria and their viruses.

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Dr Sarah Saunderson, Microbiology and Immunology
Mentor: Dr James Ussher

Exploiting the tumour microenvironment for safer antibody-based immunotherapy
$300,000

Antibody-based targeting of immune cells against blood cancers is highly effective, however treatment of solid tumours, whilst promising, is also challenging due to potential adverse effects, where normal tissue can be attacked. As solid tumours possess an acidic (low pH) microenvironment, we propose to exploit this unique feature by the modification of antibody structures to allow binding specifically at low pH, but not at the neutral pH of normal tissue.

We aim to modify both antibodies currently in use within clinical trials to increase their safety, but also to discover novel antibodies that naturally bind exclusively at low pH. In addition, we will genetically engineer immune cells to display both a receptor to target cancers, as well as a naturally occurring pH-dependent protein receptor to act as a safety switch. This will ensure the anti-cancer immune cell will only be capable of attacking the tumour cell when it receives two signals, that is the recognition of the cancer cell and the presence of low pH.

The work will increase the clinical safety of antibody-based treatment of solid tumours for improved patient outcomes.


For further information, contact:

Professor Richard Blaikie
Deputy Vice-Chancellor (Research)
Email richard.blaikie@otago.ac.nz

Liane Topham-Kindley
Senior Communications Adviser
Tel +64 3 479 9065
Mob 021 279 9065
Email liane.topham-kindley@otago.ac.nz

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