Thursday, 3 November 2016 2:38pm
University of Otago researchers have been awarded more than $13.7m in the latest annual Marsden Fund round to undertake 23 world-class research projects that push the boundaries of knowledge in their fields.
The innovative Otago projects will be led by researchers from 14 different departments across the University.
The Marsden Fund supports excellent investigator-initiated research in science, engineering, maths, social sciences and the humanities in New Zealand.
Otago projects funded in the latest round include investigations ranging from exploring the origins of New Zealand’s pre-European musical instruments to studying the massive undersea volcanic eruption in the Kermadec arc that produced a 400km2 pumice raft in 2012.
Other projects include investigating a TB bacterium protein that may provide a new target for drugs that rapidly treat the disease, how an embryo’s genome is activated, and the neural mechanisms behind persistence and quitting behaviours.
Otago recipients’ projects are also focusing on the role of placental genes in cancers, using gene editing technology to study the brain’s master control of fertility, and the use of nanoparticle catalysts to remove nitrate from groundwater, among others. A full list appears below.
Deputy Vice-Chancellor (Research & Enterprise) Professor Richard Blaikie warmly congratulated the Otago recipients on their outstanding performance in this year’s round.
“Our researchers’ stellar success reflects the excellence of the proposals they have put forward for this extremely competitive fund,” Professor Blaikie says.
The researchers represent a range of Departments including Anatomy, Chemistry, Computer Science, Geology, History, Microbiology and Immunology, Music, Theatre and Performing Arts, Pathology, Philosophy, Physiology, Psychology, Women’s and Children’s Health, and Zoology.
Professor Blaikie says it is very pleasing that nine of the Otago projects are ‘Fast-Start’ grants designed to support outstanding early-career researchers.
“From these up-and-coming researchers will come the University’s research leaders of tomorrow so it is wonderful to see their important work recognised and supported through the Fund.”
All 23 projects run for three years and the funding amounts are spread over this period.
For more information, contact:
Professor Richard Blaikie
Deputy Vice-Chancellor (Research & Enterprise)
University of Otago
Tel 03 479 8513
University of Otago
Tel 03 479 5016
Otago’s Marsden recipients:
Drinking for two: Central resetting of water balance in pregnancy and lactation
Pregnant women retain water during pregnancy to ensure an adequate blood supply for the developing baby and to prepare for milk production during lactation. Water is retained by increasing the secretion of vasopressin, a hormone that promotes water reabsorption in the kidneys. Normally, dilution of body salts by water retention decreases vasopressin secretion, but this doesn’t happen in pregnancy or lactation. While it has been known since the 1980s that altered vasopressin secretion resets water balance during pregnancy, the mechanisms that cause this resetting are still unknown. Our new data show that vasopressin-secreting cells are more sensitive to salt during lactation and so this might be the mechanism that resets water balance during pregnancy. Therefore, we will determine how vasopressin cells increase their responsiveness to salt in pregnancy to prepare women for successful pregnancy and lactation.
The origins and development of pre-European contact musical instruments in Aotearoa (New Zealand), Rekohu and Rangiaotea (Chatham and Pitt Islands)
This research addresses a significant problem of culture change in Polynesian ethnomusicology and anthropology. We aim to discover how the first southern Polynesian colonists of Aotearoa, Rekohu and Rangihaute – and their descendants – adapted tropical musical instruments and traditions to the new resources of a large, cool-seasonal continental island group. We ask: what stayed the same? What changed, where, how and why? In addition to employing a range of traditional research methods (ethnographic interviews, visual comparisons, archaeological dating, literary research), this research will be the first to create 3D models of taonga pūoro based on CT scan data. We will also undertake the most in-depth experimental organological research to date (based on all existing sources of evidence) to create new knowledge of Moriori musical instruments. In filling a substantial knowledge gap concerning the origins and development of taonga pūoro, our findings will have significant implications for wider studies of the history of Aotearoa, Rekohu and Rangihaute, enabling theories regarding patterns of Polynesian migration and cultural development to be tested. The comparative nature of this research, and its focus on indigenous material cultures, makes it of national and international significance.
Optical Network-on-Chips (ONoCs): Architectures and Routing Algorithms for Ultra High-Throughput and Energy-Efficient On-Chip Communications
$300,000 - Fast Start
Nowadays microprocessor development has moved into a new era of many-core on-chip design, with tens or even hundreds of cores fitting within a single processor chip to speed up computing. However, conventional electrical interconnect for inter-core communication is limited by both bandwidth and power density, which creates a performance bottleneck for microchips in modern computer systems - from smartphones to supercomputers, and to large-scale data centers. Optical Network-on-Chip (ONoC), a silicon-based optical interconnection among cores at the chip level, overcomes the limitations of conventional electrical interconnects by supporting greater bandwidth with less energy consumption, and opens the door to bandwidth- and power-hungry applications such as big data analysis and general artificial intelligence. However, existing ONoC designs do not fully take the advantages of optical communication to maximize performance and save energy. This project will develop scalable architectures by introducing software-defined networking concept to ONoCs, and design efficient routing and wavelength assignment algorithms specific for ONoCs, aiming to achieve >10 fold increase on on-chip communication throughput and >5 fold reduction on energy consumption. This project will advance the state-of-the-art theories and techniques for on-chip processor design, and will foster new knowledge into computer networking/architecture, high performance/green computing, and network embedding theory.
How does the Earth stop Global Warming? Testing climate stabilisation during ‘hyperthermal’ events
$300,000 – Fast Start
The Earth is in the midst of a climate crisis, with a carbon cycle disturbance comparable to those that drove biological turnover and even mass-extinction events in geological history. The side-effects of warmer global temperatures are already occurring, including ocean acidification, toxic phytoplankton blooms, and expansions of oxygen deprived conditions in the oceans. It is less well known that these threats are also negative feedback mechanisms which remove carbon from the atmosphere, and eventually re-stabilise the climate on geological timescales. The climate recovery process, however, is poorly constrained, and it is not known exactly when or how the natural climate system will return to ‘normal’. Anthropogenic activity might have even delayed the next natural glaciation cycle. We will use novel geochemical proxies to trace the action of negative feedback mechanisms during periods of past global warming. These will be applied to a series of events that represent a range of CO2 emission scenarios, analogous to those we face in the future. We will constrain the feedback mechanisms of the climate system to better understand the lifespan of human-induced climate change, providing crucial boundary conditions for modelling future climate scenarios.
Unraveling the key role of cytochrome bd oxidase in antimicrobial lethality in tuberculosis
The emergence and spread of drug-resistant tuberculosis threatens to return us to the pre-antibiotic era for this disease. New research on Mycobacterium tuberculosis has revealed that the respiratory protein cytochrome bd is required for mycobacterial persistence during antibiotic therapy, leading to the hypothesis that cytochrome bd inhibition would provide a new pathway for the rapid treatment of tuberculosis. We will employ molecular biology and structural biology to address this hypothesis. Our findings may be applicable to other bacterial pathogens that use cytochrome bd to survive during infection and lead to a new class of compounds targeting bacterial respiration in host tissues.
The genes of life and death: a role for placental-specific genes in cancer?
Invasive cancers are hard to treat. If we determine how cancer cells become invasive, then we will discover new strategies for early diagnosis or treatment. Good models for cancer invasion in humans are rare, but remarkably, the human placenta could be an excellent model for cancer because of its invasive features. The placenta invades the adjacent uterus, like cancer erodes into surrounding organs. It also takes hold of the immune system to prevent rejection of the fetus, just like cancer controls the local immune response. Intriguingly, placental and cancer cells share a genetic phenomenon that we do not understand - they fail to silence virus derived DNA sequences, known as retrotransposons, that are normally silenced in healthy tissues. Retrotransposon unsilencing is usually associated with gene disruption, sometimes causing cancer. However, in the placenta, retrotransposon unsilencing creates new genes that are essential for placental function. We have evidence that these placental genes are activated in cancer, and believe retrotransposons may offer powerful perspectives on cancer prevention and treatment. By using the placenta as a model for malignancy, we aim to determine the implications of retrotransposon activity in cancer and expect to identify new genes that control cancer invasion.
A green approach to denitrification of water
$300,000 – Fast Start
Excessive use of agricultural fertiliser has greatly increased the amount of reactive nitrogen in the biosphere in recent years. Nitrate, the most oxidised form of reactive nitrogen, is the main nitrogen-containing pollutant present in groundwater. With the persistent intensification of agriculture and the ever-increasing demand for clean water, an efficient method for denitrification is urgently required.
Catalytic denitrification is a particularly promising method as it can in principle convert harmful nitrate into harmless molecular nitrogen, quickly and without dangerous byproducts. The use of nanoparticles as catalysts is especially exciting as they can exhibit unique reactivity compared with conventional catalysts and much less of the catalytic material is required.
In this proposal we will use a combination of novel computational techniques to investigate the rate and products of catalytic denitrification using nanoparticle catalysts. The ultimate goal of our research is to identify the optimum nanoparticle catalyst for quick and safe removal of nitrate from drinking water. Our work will directly guide the future technology for denitrification.
Parasitic Puppeteers – How do They Pull the Strings?
Parasites can have profound effects on the animal hosts they invade, manipulating host biology with exquisite precision to enhance host-to-host transmission. One of the most extraordinary of these host manipulations is the water-seeking behaviour that some nematodes and hairworms induce in their hosts so that the worms might exit the host and reproduce. The process is the stuff of science fiction; the worm hijacks the host’s central nervous system forcing it to seek water. Once water is found the adult worm, often many times the size of the host, emerges, sacrificing the host. This amazing alteration in behaviour is induced by parasitic worms spanning two phyla (Nematoda and Nematomorpha) and is observed in a variety of arthropod hosts, notably crickets, weta, earwigs, and sandhoppers, leading us to hypothesise that a common and conserved mechanism is being utilised by the parasites to induce this behaviour in their hosts. Here we propose to couple field and laboratory studies of two phylogenetically distinct hosts and their parasites, with powerful genomic and bioinformatic comparisons to elucidate the trigger and genetic cascade through which these parasitic puppeteers elicit this highly conserved, yet astonishing behavioural response.
Growth factors mediating prolactin-induced neurogenesis in the adult brain
The aim of this project is to investigate the mechanisms by which the anterior pituitary hormone prolactin stimulates neurogenesis in the adult brain. The neural stem-cells do not express the prolactin receptor, but high expression is found in the choroid plexus, a structure that is considered part of the neurogenic niche. Using RNASeq to identify prolactin-responsive transcripts in the choroid plexus, we have discovered that prolactin induces expression of several growth factors. Here, we propose to investigate the hypothesis that these prolactin-sensitive growth factors secreted from the choroid plexus mediate the actions of prolactin to stimulate neurogenesis in subventricular zone of the maternal brain during pregnancy. We will measure expression of specific growth factors in the choroid plexus during pregnancy, and then determine whether expression of these growth factors changes in mice specifically lacking prolactin receptors in the choroid plexus. We will then investigate whether conditional deletion of specific growth factors in the choroid plexus abolishes the prolactin-induced increase in neurogenesis that normally occurs during pregnancy. The study will enhance our understanding of factors regulating the neurogenic niche in the adult brain, an area of intense interest in neuroscience because of its potential roles in neural plasticity and repair.
In vivo gene editing with CRISPR to define estrogen feedback in the brain
Circulating levels of the ovarian hormone estrogen act on the brain to control fertility. A group of brain cells called the gonadotropin-releasing hormone (GnRH) neurons are responsible for controlling fertility in all mammals including humans. At present, the cellular pathway through which estrogen modulates the activity of GnRH neurons in unknown. This project intends to determine precisely which brain cells are responsible for detecting estrogen levels in the blood and transmitting this information to the GnRH neurons. We will use a novel application of CRISPR-Cas9 gene editing to delete estrogen receptors from GABA, glutamate or kisspeptin neurons located in two specific brain regions of the mouse. This research will develop world-leading in vivo gene editing technology for neuroscience within New Zealand and elucidate the mechanism of "estrogen feedback" to the GnRH neurons. This information will underpin the development of new strategies for helping infertile couples as well as the development of safer contraceptive agents.
Quit or persist? The neural mechanisms of forfeit behaviour
It's hard to admit, but we’re all quitters. Mostly we quit minor tasks, like a difficult Sudoku, but quitting midway through more important endeavours can hinder personal and professional well-being. In excess, quitting can characterise clinical disorder. Why does our brain sometimes signal us to quit, even when we know perseverance will lead to a better outcome? While neuroscientists have made significant advancements in understanding how the brain formulates goal-directed behaviour, the neural mechanisms that drive quitting behaviour are not well-understood. Here we will use an animal model to test the hypothesis that quitting relies on two specific brain regions: anterior cingulate cortex (ACC) and anterior insula (AI). The ACC is known to provide signals important for choosing and pursuing effortful goals. In contrast, the AI is activated by frustration and fatigue, two key factors which can prompt quitting. Using neural recording and stimulation, we will investigate whether quitting behaviour is modulated by a dynamic interplay between an ACC ‘persist’ signal and an AI ‘quit’ signal. Our project will provide scientists and clinicians with mechanistic insight regarding how the brain formulates quitting behaviour, which will enable novel therapies to be developed to reduce maladaptive quitting behaviours and increase well-being.
Becoming master of your destiny: insights into genome activation from nuclear structure
When a zygote forms, its newly-minted genome is kept mostly inactive at first. At a defined timepoint, the zygotic genome becomes active and is transcribed. For the first time, the embryo becomes master of its own destiny. We hypothesise that formation of a transcription-competent, three-dimensional (3D) nuclear structure triggers zygotic genome activation and predicts developmental trajectory. Using cutting-edge genomics techniques that capture nuclear structure, we will test our hypothesis in zebrafish embryos. We will also use live imaging of zebrafish embryos and individual cells as they undergo genome activation, to observe visible changes in the nucleus as genes are switched on. Our overall aims are 1) To discover the transcription-permissive 3D nuclear structure underpinning zygotic genome activation, and 2) to disrupt 3D nuclear structure and determine the consequences for zygotic genome activation. Our research will provide the first evidence for how 3D nuclear structure places an animal under the control of its own genes for the first time, and will determine how important nuclear structure is for gene activation. Determining how the zygotic genome is at first held inactive, and how it rapidly becomes activated, will provide new insight into the very beginnings of life.
Acute Mental Health Wards: Therapeutic Spaces of Stigmatising Places?
$300,000 – Fast Start
During the twentieth century, isolated rural mental asylums were replaced by community based psychiatric care and acute mental health wards attached to many of our urban hospitals. Segregation from society was an overt goal of the original institutions, and was considered to support the aims of treating and managing mental illness. Contemporary mental health practice prioritises integration with society as a key part of treatment. Yet to most of us the modern acute ward remains as much of a mystery as the asylum was. An acute ward is a publicly funded but private space with restricted access. Emotive media reporting on incidents involving such places has stigmatised what is intended to be a therapeutic space. So what is in the new ‘black box’ of mental health care? What is the purpose of the new psychiatric space and what is the therapeutic philosophy? What is the architectural design and social regime of these institutions based on, and what are the effects on those who use and work in them? This multidisciplinary study draws on perspectives from social science, psychiatry, nursing and architecture to understand the architectural design, therapeutic philosophy and social regime of the modern acute mental health unit in New Zealand.
Splitting up the farm? A cross-cultural history of land and inheritance in Aotearoa
$300,000 – Fast Start
The New Zealand rural sector faces a twin crisis of absentee land ownership and pressing environmental issues to which industrial farming has undeniably contributed. Settler colonial rhetoric believed that farming families provided a model for land ownership that was not only economically efficient, but socially and morally responsible. As New Zealand moves increasingly towards corporate ownership of rural land, this study asks: what is the connection between the ideology of family inheritance and care for the land? Taking an innovative multicultural approach, the research looks beyond white settler logic and widens the definition of a “farming family” to include different ethnicities, family formations and land uses. This in-depth study engages with families and communities to ascertain the practices and problems of intergenerational land transfer in two districts in New Zealand – Hokianga in the north of the North Island, and Taieri in the south of the South Island. What does guardianship of the land mean to different cultures in these districts, and how has this shaped the landscapes and waterways of Aotearoa?
Remembering together: Collective memory and collective intentionality
$300,000 – Fast Start
Collective memory has been investigated in two distinct research traditions. Psychologists have investigated remembering in small-scale groups; social scientists and humanists have investigated remembering in large-scale groups. Humanists in other disciplines have made key contributions to our understanding of collective memory, and it is imperative that philosophers, too, begin to engage with this dynamic interdisciplinary field. Philosophical theories of collective intentionality have the potential to provide key theoretical underpinnings to collective memory research. At the same time, collective memory provides an invaluable opportunity to test and refine those accounts. This project will carry out a sustained philosophical investigation of collective memory, producing a unified account of the nature of remembering at multiple scales. The account will have benefits both for empirical collective memory research and for philosophy. It will contribute to the theoretical sophistication of collective memory research by providing a framework capable of integrating existing findings and suggesting new lines of inquiry. It will contribute to the empirical sophistication of philosophical accounts of collective intentionality by bringing these into contact with rich bodies of empirical knowledge on the workings of collective memory.
Uncovering the physiological roles of the multiple NDH2 in bacterial genomes
$300,000 – Fast Start
A fundamental feature in the adaptation of bacteria to different environments is the ability to generate energy from variable sources and to sustain metabolism. A key enzyme in this adaptation is the type II NADH dehydrogenase (NDH2) that catalyzes the transfer of electrons from NADH to various quinones. This enzyme has important roles in energizing the electron transport chain and maintaining a NAD+/NADH balance for cell metabolism through NADH oxidation. Multiple ndh2 genes exist in bacterial genomes, but the reasons for this remain unknown. I will use the intracellular pathogen Listeria monocytogenes as a model system to uncover the physiological roles of each NDH2 in both the extracellular and intracellular environments, genetically, biochemically and structurally. Such understanding could provide new rationales for targeting NDH2 for antibiotic development.
Do glaciers drive diversity? Using ancient DNA to retrace the history of New Zealand’s biodiversity
$300,000 – Fast Start
Scientists have long been intrigued by the biological effects of glaciation in New Zealand and beyond. Glaciers are traditionally seen as destructive forces for ecosystems, with ice sheets having eliminated biodiversity across extensive regions of the globe. By contrast, new evidence emerging from temperate mountain systems, including New Zealand’s Southern Alps, suggests glaciation may be a key evolutionary force structuring biodiversity along mountain chains, with speciation driven by isolation in narrow refugia. This research programme will test for ‘real-time’ range-shifts and diversification events associated with New Zealand’s Last Glacial Maximum (34-18 kya), using ancient-DNA of iconic species from multiple unique time-series of sediment cores and sub-fossil bones. Broadly, this study will use state-of-the-art tools to track phylogenetic, ecological, demographic and biogeographic shifts across recent glacial-interglacial cycles. This multi-disciplinary approach combines a wealth of sub-fossil samples, sediment cores and genomic resources - a unique system that will reconstruct the recent evolutionary history of NZ’s iconic biota.
Bones under pressure. How does the skeleton sense gravity?
The human skeleton responds to force and movement by building stronger bone. How these forces are sensed at a cellular level and translated into a biochemical response that results in stronger bones is unclear. We have discovered that mutations in two genes subvert this mechanism resulting in excessive bone formation indicating that they connect to form this biological mechanosensor. Using genetic, animal model and biochemical approaches we will describe the architecture of this force transducing apparatus that is key for the maintenance of bone health over the lifespan.
Silencing unwanted expression in molecular circuits using naturally evolved solutions
Synthetic molecular circuits can be assembled that carry out novel reactions and process simple computations. However assembling complex circuitry presents significant hurdles, as stochastic biological fluctuations (noise) can activate molecular switches in the absence of stimuli. Furthermore rapid protein inactivation is critical for dynamic circuits to function correctly, and if proteins are slow to degrade, the circuit may slow down or stop functioning altogether. Currently there are very few ways available to inactivate regulators once they are expressed. We have discovered a novel “antiactivator” protein, QseM, that tightly suppresses activation of a natural quorum-sensing circuit through binding and inhibition of two distinct transcriptional activators, and is impervious to noise. We will solve the 3D structure of QseM and characterise its antiactivation mechanism against the two targets using in vivo and in vitro approaches. ‘Proof of principle' for the utilisation of QseM in synthetic biology will be demonstrated by both constructing artificial antiactivator targets from components commonly used in synthetic circuits, and by constructing a synthetic and controllable genetic toggle switch based on quorum sensing activators and their cognate antiactivators.
Epigenetics and Evolutionary Theory
Epigenetic changes do not affect the DNA sequence of an individual. Rather, a variety of removable chemical mechanisms temporarily mark the genome, thereby modifying expression of the genes. Appropriate epigenetic markings in different tissues at different life stages are critical in the correct development and function of every individual organism. Intriguingly, we have recently discovered that, instead of being reset every generation, some epigenetic marks can be passed on unchanged from one generation to the next. Moreover, individuals in a population may differ from each other in their epigenetic markings: just as natural populations exhibit genetic variation, so do they harbour epigenetic variation. This project asks how we can explain this transgenerationally inherited epigenetic variation in natural populations and what might be the consequences for evolution. The researchers will construct and analyse new mathematical models to investigate these matters, validating these models with data from real examples, and using the models to make novel predictions about the properties of epigenetic variation in nature. Thus, this research will lead to a significantly improved appreciation of a fundamental feature of evolution and a more accurate description of inheritance in all its forms.
Why do inbred males fire blanks? Unravelling the relationship between inbreeding and infertility
$300,000 – Fast Start
Inbreeding negatively affects a wide range of life history traits in taxa as diverse as humans and plants. Mitigating the effects of inbreeding depression has been a key focus in animal husbandry and horticulture for millennia and, more recently, inbreeding has become a key topic in conservation science. It is well known that inbreeding negatively affects male fertility across a variety of taxa, but this phenomenon has rarely been examined in species where males are the homogametic sex (e.g., birds), or in the wild. While several sperm quality traits are known to be depressed by inbreeding (sperm morphology, motility, and DNA fragmentation) the interplay between these traits remains unexplored. The common fragility of male fertility suggests inbreeding disrupts a conserved set of genes across taxa, but these genes are yet to be unidentified. We will use a novel combination of genotyping by sequencing, computer assisted sperm analysis, and DNA fragmentation assessment to conduct a comparative study of inbreeding depression of male gamete quality in New Zealand's birds – the first such study in any wild system. We aim to elucidate the relationship between inbreeding and sperm quality, and identify candidate genes that might be responsible for infertility in inbred males.
Hypothalamic Inflammation: Cause of leptin resistance and obesity?
Loss of response to the body weight regulatory hormone, leptin, is regarded as the hallmark for the development of obesity. Understanding the origin of this leptin resistance is widely considered as the key to therapeutic interventions to treat obesity. The aim of this proposal is to test whether leptin resistance results from the combined action of hypothalamic inflammation and hyperleptinemia, associated with increased adiposity, thereby contributing to obesity. Mechanistic insights into the interaction of inflammatory pathways in the hypothalamus that are activated by saturated fats and leptin will improve our knowledge about the pathogenesis of obesity.
Digging into the biggest explosive submarine eruption ever “seen” to understand seafloor volcanism
This project exploits an unparalleled opportunity that we will use to gain a rigorous understanding of how explosive volcanism operates in the deep sea. In 2012 Havre seamount on the Kermadec arc north of New Zealand produced the largest submarine eruption known in history, scaling with Mt St Helens' stratosphere-piercing 1980 Plinian eruption on land. Eruptions to the surface from such water depths were unknown, yet Havre produced a 400 km2 pumice raft and vapour eruption column. A US-funded research cruise used deep submergence vehicles Jason and Sentry to provide a uniquely detailed, metre-scale resolution, topographic map of the rhyolite caldera volcano and 2012 eruptive features, and an extraordinary suite of samples collected systematically from dive-paths chosen and sites identified as the new map was constructed. The samples acquired during seafloor observation, and the amazing map itself, provide context for the proposed fragmentation experiments, heat-transfer experiments, and thermal column modelling, and will in combination reveal the factors modulating the eruption dynamics of explosive submarine eruptions. Nothing like this eruption’s scale, the cruise’s dataset, or the intensive multinational follow-up study has precedent with any previous explosive submarine eruption, and results of the work will be a touchstone for all future studies.
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