HRC grants $40m to Otago research tackling issues from climate change to heart failure

Climate change and its impact on people's health and using DNA to help predict who may suffer heart failure are just two of many University of Otago-led research projects being funded this year by the Health Research Council to the tune of more than $40 million.

Associate Professor Simon Hales.

Associate Professor Simon Hales and his team from the University of Otago, Wellington, will receive $1,190,579 over three years to investigate the relationship between extreme rainfall events and water-borne gastroenteritis infections.

“There have been several severe flood events in recent years, leading to both short-term and long-term impacts. A major outbreak of campylobacter in Havelock North was linked to contamination of a local water supply following heavy rainfall,” Associate Professor Hales explains.

“In this study we will identify times, such as following heavy rainfall, and locations, such as communities using smaller untreated ground-water supplies where risk of waterborne enteric disease may be increased.”

The researchers plan to define policy-relevant parameters for water regulators, including local climate thresholds for use in early warning systems and national maps of community vulnerability, both currently and under scenarios of future climate change and freshwater policy.

“It is very encouraging that the HRC has recognised the importance of research on the health impacts of climate change,” Associate Professor Hales says.

The HRC's $81 million investment in new research projects and programmes was announced earlier today by the Minister for Research, Science and Innovation, Megan Woods. The University of Otago receives $40.03 million in total.

Dr Anna Pilbrow.

At the University of Otago, Christchurch, Dr Anna Pilbrow and her research team are looking to use an individual's DNA to help predict which patients develop heart failure after a heart attack, receiving $1,193,680 for their three-year project.

“People who have a heart attack are at much greater risk of developing heart failure, but it's difficult to predict who might be affected,” Dr Pilbrow explains.

“Our study aims to test whether information in a patients' DNA can help us predict who might develop heart failure after having a heart attack. We'll be analysing the DNA of a large number of patients and compiling the data into a 'genetic risk score'. We plan to test the clinical utility of this genetic risk score in patients from New Zealand and overseas.”

The University of Otago received its most significant level of funding in recent years from the HRC for research 'projects' with $35,077,887 distributed to 30 projects. This is a major increase from the past five years where funding has varied from $15 to $19 million.

In addition, Professor Janet Hoek and her colleagues from the University of Otago, Wellington, received almost $5 million for a five-year 'programme' aiming to close smoking disparities, particularly for Māori and Pacific people. In total, the University receives $40 million from the HRC.

University of Otago Deputy Vice-Chancellor, Research and Enterprise, Professor Richard Blaikie, says it is significant that the HRC has this year funded so many Otago research projects.

“We are grateful to the HRC for its ongoing support. To see our project funding almost double from last year is testimony to the important health research our academic staff are undertaking.

“It is also exceptionally pleasing to see the HRC provide significant support for emerging research leaders amonst these projects, which bodes well for the future.”

For further information contact

Associate Professor Simon Hales
University of Otago, Wellington
Email simon.hales@otago.ac.nz
(Currently in Asia with a five hour time delay from NZ, available for interview via Skype)

Dr Anna Pilbrow,
University of Otago, Christchurch
Email anna.pilbrow@otago.ac.nz

Liane Topham-Kindley
Senior Communications Adviser
Tel +64 3 479 9065
Mob +64 21 279 9065
Email liane.topham-kindley@otago.ac.nz

Research to receive HRC Programme funding

Professor Janet Hoek
University of Otago, Wellington
Whakahā o Te Pā Harakeke
60 months, $ 4,949,736.70

The Whakahā o Te Pā Harakeke programme represents a collaboration that will develop and improve evidence designed to close smoking disparities, particularly for Māori and Pasifika, enhance how tobacco control evidence is used in decision making, and accelerate progress towards a Smokefree Aotearoa. We will achieve this goal by using mixed method approaches that combine population-level analyses of existing and potential interventions with in-depth enquiries that probe how reducing tobacco's appeal, affordability and accessibility has impacted communities and whanau. Analysing the complex tobacco control system will evaluate knowledge translation routes, consider barriers and enablers within these, and identify how evidence can more effectively accelerate reductions in smoking prevalence and reduce entrenched disparities. By partnering with Hāpai te Hauora and Kokiri marae, we will draw on community knowledge, build research capacity, and create unique opportunities to engage across the stakeholder spectrum and address the pressing health inequities caused by smoking.

Researchers to receive HRC Project funding

Dr Philip Adamson
University of Otago, Christchurch
Duration of Dual Antiplatelet Therapy in Acute Coronary Syndrome (DUAL-ACS)
48 months, $ 1,549,999.75

After a heart attack, patients are prescribed two drugs to “thin” the blood and to prevent further heart attacks. However, thinning of the blood also means that bleeding is more likely, and with time, this can have potentially life-threatening consequences. We therefore propose a nationwide study that will address this major concern by following what happens to patients if we use two different durations of treatment. The goal of the study is to determine how long we should give blood thinning drugs so that heart attacks can be avoided without undue risk of bleeding. This will address a major international controversy and define how we best treat patients following a heart attack in order to maximise the benefits and minimise the risk. It will also have benefits for New Zealand's health system by potentially avoiding the costs of unnecessary and potentially harmful prolonged treatment.

Dr Martin de Bock
University of Otago, Christchurch
Automated Insulin Delivery for Type 1 Diabetes utilizing open source technology
36 months, $ 1,317,623

Automated insulin delivery (or closed loop technology) for type 1 diabetes has heralded a new era of treatment, delivering improved glucose management and quality of life. While commercial systems are existent overseas, cost will be an ongoing barrier to access this technology in New Zealand. However, an open access automated insulin delivery algorithm has been in development for years, but has previously required "hacking" of commercial insulin pumps, causing medicolegal concerns. A recent insulin pump innovation has opened the opportunity to utilise the open access technology, letting patients "close the loop" without voiding their insulin pump warranty. In this project we will compare glycaemic control, quality of life and health economics of this technology compared to standard insulin pump therapy in a multi-centred randomised controlled trial, in both children and adults with type 1 diabetes. Positive findings will lay the foundation for New Zealanders to access this life changing technology.

Professor David Bilkey
University of Otago, Dunedin
A Novel Biomarker for Preclinical Drug Development in Schizophrenia
24 months, $ 489,282.20

Current drug-based therapy for schizophrenia, a disorder of brain function, is only moderately successful and has changed minimally over the past 40 years. This situation has arisen because of our limited understanding of the links between brain activity and psychological-level symptoms and how this knowledge is incorporated into our current preclinical models of the disorder. Here we aim to bridge this gap by examining a specific brain mechanism that appears to underlie the sequential encoding of information in the hippocampus. We propose that a disturbance in this mechanism underlies the disorganised thought symptoms observed in schizophrenia. This brain mechanism is ideally situated for use as a biomarker for preclinical drug testing and screening. We will, therefore, examine the responses to current known antipsychotics in preclinical models of schizophrenia, and then use our knowledge of this system to test novel drugs for their putative therapeutic potential in reorganising neural activity.

Professor Sarah Derrett
University of Otago, Dunedin
Prospective Outcomes of Injury Study: 10 years on (POIS-10)
36 months, $ 1,193,001

In New Zealand, injuries are prevalent, costly, and burdensome – causing 34 per cent of disability. Our earlier Prospective Outcomes of Injury Study (POIS) investigated outcomes to 24 months post-injury; few studies have investigated outcomes beyond 24 months. Ten years on, POIS-10 provides a unique opportunity to: 1) investigate a range of disability, health and wellbeing outcomes to 12-years post-injury, and 2) identify factors predicting such outcomes. POIS-10 will invite 2121 people (including 358 Māori) who completed a 24-month POIS interview; anticipating 75 per cent participation (n=1591). POIS-10 data will be collected via in-depth interviews, and linked ACC and health administrative e-data. POIS-10 will result in benefits for injured people, including Māori, through increased understanding of mechanisms to improve long-term post-injury outcomes. Benefits of POIS-10 are enhanced by our partnership with ACC and expert advisors in development of an early care prediction tool (INJECT), informing the implementation of effective interventions to improve outcomes.

Dr Allamanda Faatoese
University of Otago, Christchurch
Environmental Effects on Cardiometabolic Biomarkers in Pacific Peoples
36 months, $ 594,804

Improved screening and management of cardiometabolic conditions have resulted in small health gains for Pacific peoples. Innovative approaches to reduce this burden in the Pacific population are required. The Pasifika Heart study documented cardiometabolic profiles for 200 Pacific adults living in Christchurch. High rates of cardiometabolic risk factors (particularly diabetes and obesity) were observed. Nutritional intake analysis showed low fruit and vegetable intake corroborated by vitamin C levels. Genetic variants associated with type 2 diabetes identified from international studies were not highly informative to the susceptibility of Pacific peoples to diabetes. We propose to investigate the interplay between environment and genetic factors. Epigenetics, the external modification of DNA by environmental exposures controls gene expression. We will explore the relationships of genome-wide DNA methylation (epigenetic marker), lifestyle factors and biomarkers in this cohort. Methylation data will enable genetic pathways associated with cardiometabolic risk to be elucidated for Pacific peoples.

Professor Michelle Glass
University of Otago, Dunedin
Characterisation of synthetic cannabinoid signalling bias and toxicity
36 months, $ 1,172,581

Novel psychoactive substances containing synthetic cannabinoids are the most rapidly growing class of recreational drugs. Synthetic cannabinoid products have effects similar to those of natural cannabis, yet, these drugs are more potent and dangerous, and have been associated with serious adverse effects, including over 20 deaths in New Zealand in the past year. In this application we aim to understand the diverse molecular signalling of these compounds, and correlate these with the adverse effects. This knowledge would inform policy around these compounds, and treatment strategies as well as broadening our understanding of the endocannabinoid system.

Associate Professor Simon Hales
University of Otago, Wellington
Climate change, extreme rainfall events and enteric disease outbreaks
36 months, $ 1,190,579

Observed climate trends in New Zealand are consistent with projected effects of global climate change. The summer of 2017-2018 was the hottest on record. There have been several severe flood events in recent years, leading to both short term and long term impacts. A major outbreak of campylobacter in Havelock North was linked to contamination of a local water supply following heavy rainfall. Resilience to extreme climate events depends strongly on local factors, but these have not been systematically studied in New Zealand. In this study, we will quantify relationships between extreme rainfall events and water-borne enteric infections and investigate the impact of local factors including land use, source water and type of water supply. We will define policy-relevant parameters for water regulators, including local climate thresholds for use in early warning systems and national maps of community vulnerability, both currently and under scenarios of future climate change and freshwater policy.

Professor Bob Hancox
University of Otago, Dunedin
A Randomised Controlled Trial of Beta-blockers in COPD
60 months, $ 1,439,384

Many patients with chronic obstructive pulmonary disease (COPD) also have heart disease. Beta-blockers are an important treatment for heart disease that reduce mortality, but these drugs are usually avoided in patients with COPD because of concerns that it might make their lung disease worse. It is now thought that cardio-selective beta-blockers, which have less effect on the lungs, are probably safe for patients with COPD, but no studies have compared the balance of risks and benefits in these patients. This is a randomised, placebo-controlled trial of the cardio-selective beta-blocker bisoprolol for patients with COPD to assess the effects of beta-blockers on cardiac and respiratory health and overall survival. The study will be conducted at multiple centres in New Zealand and Australia.

Associate Professor Anne-Louise Heath
University of Otago, Dunedin
Novel methods of infant feeding in New Zealand – cause for concern or optimism?
36 months, $ 1,185,359

Researchers, health professionals, and policy makers know surprisingly little about how and what infants are fed during their remarkable journey from consuming a 100 per cent milk diet at birth, to consuming the same foods as their family around their first birthday. In fact, we don't know what babies are eating in New Zealand even though there has been a revolution in infant feeding with domination of the market by baby food “pouches”, and massive popular uptake of Baby-Led Weaning (BLW), a virtually unstudied approach to introducing solids in which babies feed themselves 100 per cent finger foods - from the start. The First Foods NZ study will determine the impact of pouches and BLW on iron deficiency, growth, choking and dental health in an observational study of 625 Dunedin and Auckland infants. The results will enable the Ministry of Health, health professionals, and Plunket to advise parents on how to introduce solids safely.

Professor Janet Hoek
University of Otago, Wellington
Developing optimal strategies to support smoking cessation among RYO users
36 months, $ 1,195,934

New Zealand has among the highest rates of roll your own (RYO) tobacco use internationally; RYO causes particular harm to Māori, young adults and people experiencing lower prosperity. Increasing the costs of RYO tobacco has led some smokers to forgo essential items and stimulated calls for new approaches. Using a parallel process for Māori and non-Māori, we will develop and test RYO-specific high-affect warnings, and assess how these affect users' beliefs and quitting behaviours when combined with efficacy messages that enhance quitters' confidence. Whānau and in-depth interviews will identify optimal warnings and efficacy messages; a survey will test the communication effectiveness of these stimuli, and a choice experiment will compare individual stimuli and interactions between these. Conducted in partnership with Hāpai te Hauora, our research will provide the first evidence of how tailored RYO warnings and efficacy messages influence cessation-related beliefs and behaviours among groups most affected by RYO use.

Associate Professor Julia Horsfield
University of Otago, Dunedin
A novel genetic mechanism in Acute Myeloid Leukaemia
36 months, $ 1,177,919

Acute myeloid leukaemia (AML) is an aggressive cancer of the bone marrow with an overall survival of about 30 per cent. Outcomes for older patients are especially poor, with cure rates of only 10-15 per cent. Treatment for AML has not changed substantially in more than 30 years. Mutations in the cohesin complex occur in 12-15 per cent of people with AML, and evidence shows they are causative of AML. Cohesin brings regulatory elements, known as “enhancers”, to genes, to regulate their expression in response to signalling pathways. Wnt signalling, which is also implicated in leukaemia, is altered by cohesin mutation. In this project, we will test two hypotheses: 1. That cohesin mutation and Wnt signalling cooperate to “cluster” enhancers and drive chromosome translocation, leading to AML development. 2. That enhancer-blocking drugs will reverse these effects. The results will identify a new genetic combination as a molecular cause for AML and uncover novel options for therapy.

Associate Professor Stephanie Hughes
University of Otago, Dunedin
Dissecting the role of glial lysosome function in neurodegeneration
36 months, $ 1,199,417

Maintaining a healthy brain requires a fully functional cellular recycling system. The lysosome is the final destination of cellular waste and its dysfunction is a common feature of many neurological diseases including Alzheimer's and Parkinson's disease. Understanding how the lysosomal system functions in health and disease is critical for the development of therapies for these diseases. Most of our current understanding is based on analysis of lysosomes in neurons, however there are other important cells in the brain that have received little attention. Our goal is to determine the specific roles of these support cells in the brain on the development of neurodegenerative disease and how defects in the lysosomal system in these cells impacts on normal function of neurons.

Dr Karl Iremonger
University of Otago, Dunedin
A neural circuit to suppress stress in motherhood
36 months, $ 1,167,222

Prolactin is a hormone that drives many neural adaptations during pregnancy and lactation, including the suppression of behavioural and endocrine stress responses. This adaptation benefits the mother and protects the child from excessive stress during the perinatal period. Corticotropin-releasing hormone (CRH) neurons control the neuroendocrine stress response. Prolactin inhibits the output of this neural network, however, CRH neurons do not express prolactin receptors, indicating that prolactin signalling must be relayed from upstream neural populations. The medial preoptic area (MPOA) has one of the highest densities of prolactin receptors in the brain and also sends direct projections to CRH neurons. This current project will determine how prolactin sensitive neurons in the MPOA control CRH neurons and hence stress responses during pregnancy and lactation. This will give important insight into a form of neural plasticity essential for safeguarding the health of mother and child during the perinatal period.

Dr Anne-Marie Jackson
University of Otago, Dunedin
Tangaroa Ara Rau: Māori water safety programme for whānau
36 months, $ 1,192,263

Wai (water) is central to Māori culture, yet Māori have disproportionately high rates of drowning in Aotearoa. The need for a Māori water safety programme for whānau Māori is an urgent one. Here, Māori researchers will work alongside Tangaroa Ara Rau – a collective of national Māori water safety practitioners and researchers - and three Māori communities, utilising a kaupapa Māori approach to develop a Māori water safety programme. It will be tested, adapted and re-tested according to regional differences and preferences. We will also create a folio of evidence to inform advocacy for free water safety programmes for whānau. With a team of emerging to mid-career Māori researchers, this work will benefit communities and the Māori health research workforce. Furthermore, this research will contribute to Water Safety New Zealand's goal of zero drowning for Māori and all New Zealanders.

Mrs Bernadette Jones
University of Otago, Wellington
Te Ao Mārama: Disability perspectives of tāngata whaikaha Māori
36 months, $ 1,186,338

Indigenous people worldwide have diverse historical and contemporary impacts of disablement arising from colonisation and dysfunction that are in themselves disabling. In Aotearoa 24 per cent of the general population and 26 per cent percent of Māori self-reported as disabled in 2013. When adjusted for age, the rate of Māori disability is 32 per cent. Currently, there is a gap in Māori disability research and no accurate measure regarding the impact of disability on Māori. By using a Kaupapa Māori methodology to understand the perspectives of Tāngata Whaikaha (Māori with a disability), we aim to develop culturally appropriate approaches to measuring disability. We will accurately quantify the prevalence of “disability” among Māori and its impacts on health, wellbeing, social inclusion, and costs for Tāngata Whaikaha. Findings will then be disseminated widely so that inequities for Māori are addressed in the health and disability sectors and new knowledge can inform changes in health policy and disability services.

Professor Kurt Krause
University of Otago, Dunedin
New Drugs for the Post-Antibiotic Era by Targeting Glutamate Racemase
36 months, $ 1,199,914

There is an urgent need to develop new antimicrobials as the worldwide spread of drug-resistant bacteria threatens to create a post-antibiotic era in which diseases like tuberculosis and even routine bacterial infection cannot be effectively treated. Glutamate racemase is an essential enzyme in bacteria and is an excellent target for structure based drug discovery. We propose to use the structure of this enzyme as a scaffold for drug development in a multi-disciplinary approach that includes medicinal chemistry, structural biology, and microbial genetics. We have verified the essentiality of this enzyme in mycobacteria, solved its three-dimensional structure and identified inhibitors in preparation for initiating this project. We propose here a plan to capitalise on these advances in order to develop new drugs for tuberculosis.

Dr Alex Macmillian
University of Otago, Dunedin
Health and equity impacts of Te Ara Mua Future Streets
30 months, $ 1,185,793

Shifting short trips by car to walking and cycling would bring large benefits for health and fairness in cities. These benefits include building physical exercise back into our daily lives, improving air quality, reducing car crash injuries and improving neighbourhood social connection. Reduced car use would save families money and reduce climate pollution. This research is about how we retrofit suburbs that have been designed for car use, to make them safer, more attractive, and more convenient for walking and cycling, with a focus on what works for Māori and Pacific communities so transport investments might also in future contribute to reducing health inequalities. We have already co-designed and constructed new walking and cycling infrastructure in Māngere, Auckland and this proposal is to measure the health and fairness benefits 3.5-4 years post-intervention, comparing the outcomes with the same measures in a similar suburb without the intervention.

Sandra Mandic
University of Otago, Dunedin
Built Environment and Active Transport to School: BEATS Natural Experiment
36 months, $ 1,197,487

Physical inactivity and sedentary lifestyles among adolescents are global public health problems, which increase the risk of obesity and reduced psychosocial health. Active transport to school is a convenient way to integrate physical activity into everyday life. Several Dunedin neighbourhoods have been undergoing on-road and off-road cycling infrastructure construction since 2014 and pedestrian-related infrastructure changes in 2018, affecting six out of 12 Dunedin secondary schools. The BEATS Natural Experiment study will examine the effects of these built environment changes on active transport to school in Dunedin adolescents, and their physical activity levels, as well as their perceptions of the school neighbourhood built environment. Data will be collected through schools using published research methods. Analysis will include 2014/2015 BEATS Study data (www.otago.ac.nz/beats), and contemporary ecological models for active transport that account for individual, social, environmental, and policy factors. Findings will inform planning of future built environment and active transport interventions.

Professor Dr Neil McNaughton
University of Otago, Dunedin
Do hippocampus, insula and amygdala contribute to an anxiety syndrome biomarker?
36 months, $ 1,090,630

'Anxiety disorders' are the commonest mental disorders in New Zealand; but their diagnosis is still based on clinical symptom checklists not biological markers of specific causes. In our well-established neuropsychological theory, anxiety involves threat-approach controlled by specific brain structures in which hypersensitivity to input generates specific clinical syndromes. We have developed a specific non-invasive biomarker for threat-approach system activation in humans that shows hyperactivity in some clinical cases with source localisation to right inferior frontal regions. Our project will test this with fMRI and test for the involvement, predicted by our theory, of hippocampus, insula and amygdala. This should provide better understanding of the underlying causes of anxiety and ultimately provide targeted treatments; greatly improving treatment outcomes and cost-effectiveness.

Professor Tony Merriman
University of Otago, Dunedin
Addressing clinical questions in gout using genetic data
36 months, $ 1,198,120

In Aotearoa, 6 per cent of Māori, 8 per cent of Pacific and 3 per cent of European people have the arthritis gout and there is co-morbidity with other serious diseases, such as diabetes, heart and kidney disease. Gout is caused by an immune response to urate crystals when urate levels are elevated. Here we will use our existing large genome-wide genotyped datasets, and various genetic epidemiological approaches, to address four clinically-relevant and translatable questions. Do environmental exposures impact differently on the risk of gout according to genotype? Does gout cause co-morbidities? Can response to the common gout drug allopurinol be predicted more accurately? What is the relative contribution of diet, allopurinol, and genetics to urate levels in people with gout? Outcomes will be: more specific lifestyle advice and drug prescribing for people with gout (precision medicine); data that may support more intensive treatment to prevent co-morbidities.

Associate Professor Brian Monk
University of Otago, Dunedin
Readying next-generation antifungals for drug development
36 months, $ 1,199,967

Opportunistic invasive fungal infections (IFIs) carry high morbidity and mortality for those with co-morbidities, especially the immunocompromised, such as transplant and AIDS patients. Despite treatment with the best available antifungal drugs, approximately 50 per cent of the patients with IFIs die. The need for new, potent and inexpensive fungicides is urgent due to innate and acquired resistance to antifungal agents. This project will meet this need. We will use high-resolution structures of the antifungal target lanosterol 14α-demethylase (LDM) from a range of fungal species and humans, together with yeast-based assays, clinical isolates of fungal pathogens, and animal trials, to elucidate key features conferring antifungal specificity and that optimize broad-spectrum antifungal candidates in readiness for drug development by the pharmaceutical industry. Drug resistance will be addressed using in-house technology to identify LDM-directed fungicides and mixtures that improve potency and avoid the emergence of drug target- and drug efflux-mediated antifungal resistance.

Dr Garry Nixon
University of Otago, Dunedin
A rural-urban classification for NZ health research and policy
30 months, $ 943,443

The current Statistics NZ definition of “rural” is not designed to be used in health research. When used for this purpose it can compromise efforts to ensure equitable health outcomes and access to health services for rural people. This geographic definition does not take available health services into account and so the population defined as “rural” differs from that which actually receives rural health care. Recent evidence suggests that around 40 per cent of the people who actually access rural health services are currently classified as “urban”, and 20 per cent of those defined as “rural” actually receive urban health care. The extent of this mismatch masks any inequality in healthcare access or outcomes that may exist and hampers all current and future research. We propose to develop and validate a “fit for purpose” rurality classification and to use this to analyse current health data to better understand rural health in New Zealand.

Professor Dr Suetonia Palmer
University of Otago, Christchurch
Teaching to improve health outcomes for peritoneal dialysis: The TEACH-PD trial
60 months, $ 1,439,326

Peritoneal dialysis provides a way for patients to do dialysis at home that can be easily learned and is lower cost than hospital-based dialysis. Peritoneal dialysis may not be possible when severe infection causes complications. About 40 per cent of people starting therapy choose peritoneal dialysis, but serious complications cause patients to switch to haemodialysis. Only 16 per cent of patients who start peritoneal dialysis are using the treatment at 5 years. Patients are taught to do peritoneal dialysis independently by nursing trainers and the patient's dialysis technique is one of the most important factors to achieve dialysis longevity free from complications. Despite the critical importance of patient training, there is little evidence for the impact of effective training on patient outcomes. TEACH-PD is a randomised trial of dialysis training modules for nurse trainers and patients to identify whether a standardised curriculum helps maintain patient independence and survival better than usual care.

Professor Dr Suetonia Palmer
University of Otago, Christchurch
Serum phosphate to improve outcomes for dialysis patients: The PHOSPHATE trial
60 months, $ 1,266,603

Over 4500 New Zealanders live with kidney failure requiring treatment with dialysis or a kidney transplant. Although dialysis is life-sustaining, the death rate is unacceptably high at 13 per 100-person-years. Kidney failure disproportionately affects Maori and Pacific patients. Despite the fact that dialysis costs 1 per cent of the annual New Zealand health budget, the mortality for dialysis patients is 100 times higher than the general population. Kidney failure leads to accumulation of phosphate in blood vessels and body tissues and increases risks of death. Phosphate binders reduce phosphate absorption from the gut to lower blood phosphate levels. Despite more than 100 previous trials, the evidence that phosphate binders improve patient-centred outcomes is of low certainty. The PHOSPHATE trial is a pragmatic, multi-national randomised trial evaluating whether intensive reduction of serum phosphate levels improves cardiovascular outcomes and mortality for dialysis patients compared to a higher serum phosphate target level.

Dr Anna Pilbrow
University of Otago, Christchurch
A precision medicine approach to improving heart disease outcomes
36 months, $ 1,193,680

Mortality rates for coronary heart disease have fallen over the last 50 years. Patients now live longer following acute coronary events with many surviving to incur later adverse sequelae, especially heart failure. However, disease progression varies considerably between patients and is difficult to predict. We aim to discover what information an individual's DNA may contribute to predicting disease progression. We will establish a genetic risk score to improve on current methods of predicting progression from heart attacks to ischaemic heart failure by integrating 1) new data on how DNA variants regulate gene activity in the heart, and 2) health information from New Zealand and international cohorts. Our preliminary data indicate this approach will provide new knowledge on the mechanisms underlying heart disease. Our research has the potential to improve risk stratification and outcomes for heart patients. This project utilises existing clinical cohorts and more than 200 heart samples for which DNA has already been collected.

Professor John Reynolds
University of Otago, Dunedin
Manipulating rewards to treat maladaptive brain disorders: Focus on tinnitus
36 months, $ 1,192,994

Tinnitus, chronic pain, depression, obesity and addiction are common neurological and neuropsychiatric conditions that impose significant negative impact on individuals and society and lack effective treatments. These conditions appear to share similar abnormalities in parts of the brain network associated with reward. Brain networks can be modulated in certain conditions such as Parkinson's disease using deep brain stimulation (DBS), however there are no effective stimulation methods developed for modulating the reward network. Here we propose to develop a novel DBS approach to reverse the abnormalities in the reward network and will test the efficacy of the stimulation in a well-established animal model of tinnitus (ringing in the ears). We will also identify in which part of the brain neurons change their activity following the stimulation by using markers for neuronal activation and by recording the response of the neurons. The project will provide solid pre-clinical results for effective clinical translation.

Professor Rachael Taylor
University of Otago, Dunedin
Does a brief sleep intervention in infancy have long-term health benefits?
36 months, $ 1,190,308

Given that one in three New Zealand children are overweight or obese, research aiming to address the global obesity pandemic has increasingly focused on opportunities for prevention in early life, particularly in the “first 1000 days” (from conception to 24 months of age). Our recent trial demonstrated that children who received a brief sleep intervention in infancy had only half the risk of obesity at 2 years of age as children who did not receive the sleep intervention. More importantly, these benefits remained at 5 years of age, even though no intervention had occurred for at least 3 years. This follow-up will determine the long-term sustainability of this brief intervention, which has the potential to dramatically reduce obesity risk in children. More than 700 children will be invited to attend the 10-year-old follow-up to measure growth, body composition, sleep and physical activity patterns, eating behaviour, health and wellbeing.

Dr James Ussher
University of Otago, Dunedin
The role of microbial viability in regulating MAIT cell activation
36 months, $ 1,191,634

Mucosal surfaces are a critical interface with the external environment. The mucosal immune system must be tightly regulated to fight infection while avoiding disease-causing inflammation. Mucosal associated invariant T (MAIT) cells are pro-inflammatory, antibacterial T cells that are abundant at mucosal surfaces. While MAIT cells are primarily activated by a bacterial metabolite, we have recently found that other bacterial components also modulate their activation, and that this is dependent upon phagocytosis of intact bacteria. This suggests that the sensing of microbial viability by antigen presenting cells may be important in modulating their ability to activate MAIT cells. In this study, we will determine the importance of sensing microbial viability for MAIT cell activation, how viability is sensed by antigen presenting cells, and how viability is signalled to MAIT cells. This will enhance our understanding of MAIT cell function and inform the future development of MAIT cell-directed therapies.

Associate Professor Logan Walker
University of Otago, Christchurch
Impact of germline copy number variation on endometrial cancer risk
36 months, $ 1,145,197

Endometrial cancer is the most common gynaecological tumour in developed countries, and the incidence of this disease is increasing. The disease is associated with significant morbidity due to surgical and radiation treatment options in affected women, increased mortality for Māori, and increased incidence for Pacific women. Furthermore, a significant proportion of endometrial cancers arise in a subset of women who inherit genetic changes that increase risk of developing the disease. However, for most of these women the changes underlying their disease remain undetermined. Our proposal aims to exploit a large international collaboration to identify and functionally characterise genetic changes associated with endometrial cancer. Discoveries from this unique proposal will provide candidate risk factors for future diagnostic and treatment protocols, and provide new insights into the aetiology of endometrial tumour development.

Dr Emma Wyeth
University of Otago, Dunedin
POIS-10 Māori: Outcomes and experiences in the decade following injury
36 months, $ 1,191,067

Māori experience injury and disability inequities. Our Prospective Outcomes of Injury Study (POIS) has investigated a range of Māori post-injury outcomes to two years post-injury, adding to a current knowledge gap. Maximising the opportunity POIS provides, POIS-10 Māori aims to understand and improve long-term (12 years post-injury) outcomes and experiences (positive and negative) for injured Māori and their whānau, using key Māori models of health and well-being. We will follow-up Māori POIS participants (N=544) for POIS-10 Māori, collecting data via quantitative telephone interviews, linking ACC and hospitalisation e-data to 12 years post-injury to understand and identify the factors contributing to key outcomes; and, qualitatively explore the experiences of, barriers and facilitators of access to services, via face-to-face interviews with 15-20 purposively selected participants and their whānau. POIS-10 Māori will provide vital insights about the complex injury and rehabilitation pathway to improve long-term outcomes and experiences, and identify intervention opportunities.