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When babies lie 'back-to-back' with their mother in labour, known as occiput posterior or OP, it often obstructs the birth passage and results in operative birth. There can also be heavy blood loss, severe tears, and sometimes babies are injured or admitted to intensive care. Maternal posture may help gravity turn the baby's spine to the mother's front for safer, natural labour and birth. This study will see whether it is feasible to conduct a larger later study comparing use of semi-prone lateral posture to free posture when the baby is OP, to see if spontaneous vaginal birth is statistically more likely. Interested, eligible pregnant people at Middlemore and Auckland City Hospitals are offered a scan in labour to check baby's position. If the position is OP, they can join the study if they wish. A computer randomly assigns the posture they use. The posture is ideally used for 40 minutes or more each hour till birth. All other care is as usual. Mothers are invited to complete a post birth survey about their satisfaction with labour and their trial experience. The feasibility study will run for 6 months to recruit 50 pregnant people.

Although Huntington's disease is considered a brain disorder, our research suggests that at least some of the brain pathology may in fact originate in the liver. Huntington's disease is caused by a mutation in the 'huntingtin' gene. Individuals with the disease-causing version of the gene develop characteristic movements (chorea), as well as behavioural changes and cognitive decline over the disease course. There is currently no treatment to prevent or slow the debilitating disease course, which is on average 15 years from motor onset (typically in a person's 30's or 40's). We have discovered that levels of a metabolite called urea are elevated in the Huntington's disease brain. Urea is a waste product of normal metabolism, however excess levels of urea are toxic to brain cells and could cause brain cells to die in Huntington's disease. Intriguingly urea is made in the liver, not the brain. Our research will use cutting-edge gene sequencing technology to discover how huntingtin influences other genes to control metabolic function of the liver, and particularly urea production. We hope this will reveal disease mechanisms and potentially advocate for the trial of existing therapies that are able to reduce levels of urea and its precursor ammonia.

Group A Streptococcal (GAS) bacterial infections such as sore throats and school sores are common among school-aged children. If left untreated, these infections pose a risk of triggering acute rheumatic fever (ARF), a severe autoimmune disease. Additionally, GAS can cause severe invasive infections. These diseases are inequitably prevalent in Aotearoa's Māori and Pacific populations. While several GAS vaccine candidates are in development, none have been licensed yet, highlighting an unmet health need. The GAS pilus, a hair-like structure on the bacterium's surface, plays a crucial role in infection. Ancillary protein 1 (AP1) sits at the tip of this hair-like structure and is responsible for helping the bacteria stick to your throat or skin. Blocking this function by generating antibodies to this protein could prevent infection. The proposed research aims to identify the most effective part of the AP1 protein to use in a vaccine. We will use our established host cell binding assays and rabbit antisera to test this in a culture dish. A well-established mouse nasopharyngeal challenge model will also be used to confirm if immunisation with AP1 can prevent the colonisation of GAS in the mouse nose and throat. The significance of this research lies in its potential to develop a new vaccine against GAS, addressing a significant disease burden in New Zealand.

Platinum-based chemotherapy drugs like cisplatin, oxaliplatin, and carboplatin are vital in cancer treatment, yet their effectiveness is often hampered by severe side effects and resistance linked to elevated glutathione (GSH) levels in cancer cells. Our research aims to overcome these challenges by developing innovative platinum-based prodrugs that are selectively activated by high GSH levels in tumour cells. Building on a pilot study that created a mono-nitric oxide (NO) donor-platin conjugate prodrug—enhancing treatment efficacy but producing lower-than-optimal NO levels—we now propose developing dual NO donor-platin conjugates. These new prodrugs are designed to release higher NO concentrations, potentially increasing treatment effectiveness and providing more targeted cancer therapies while minimising harm to healthy tissues.

The menstrual cycle causes major fluctuations in hormones. Changes to progesterone and estrogen in particular are known to dramatically affect not just reproductive systems but brain function. In health, the female brain adapts to these changes, however, for females with disorders such as depression, epilepsy and schizophrenia, symptoms may get worse around menses or ovulation. Females are majorly overrepresented in adverse reactions to common medications which suggests that menstrual cycle linked hormones may not just change disorder symptoms but also the response to drug therapies. We will study how the brain’s response to drugs changes over the menstrual cycle. We are particularly interested in the serotonin system and how the menstrual cycle may change how females are affected by and process serotonergic acting drugs. We will study this by using a drug that modifies serotonergic signalling, measuring EEG and taking blood samples. This research may help to improve treatments by taking the menstrual cycle into account and potentially reduce symptoms and adverse reactions over the menstrual cycle. We will also use the findings to inform future work into developing new treatments for the debilitating menstrual-cycle related mood disorder premenstrual dysphoric disorder – a severe form of premenstrual syndrome (PMS).

Group A Streptococcus (GAS) causes many different diseases in humans. Pharyngitis and tonsillitis are rather harmless diseases, but if untreated they can develop into acute rheumatic fever (ARF) and rheumatic heart disease (RHD). ARF and RHD in Māori and Pacific peoples remain one of Aotearoa NZ’s most pressing health problems and we continue to have some of the highest rates in the world. There is currently no vaccine against GAS. We have developed a vaccine candidate (TeeVax) and have shown moderate efficacy in a mouse infection model. This vaccine was formulated with Alhydrogel 2% (alum), a commonly used vaccine adjuvant. Our results and reports from other GAS vaccine studies suggest that alum might not be ideal to adjuvant a GAS vaccine. We have recently started to collaborate with the U.S company Versatope Therapeutic which has developed a new vaccine platform. The goal of our study is to use the Versatope platform to develop a mucosa TeeVax-based GAS vaccine. The vaccine will be generated by Versatope and efficacy will be evaluated in our lab in Auckland using an established mouse nasopharyngeal colonisation models. We are also interested to analyse the specific immune responses to better understand the differences in adjuvant activities.

People living with homelessness experience a high prevalence of chronic, often untreated physical and mental health conditions. As a result, their life expectancy is 20-30-years shorter than in the housed population. Death may appear sudden but is not entirely unexpected given the health risks associated with being homeless. People typically die alone, in public spaces or in private vehicles. Advance Care Planning (ACP) is a process that provides people an opportunity to express and document their preferences for care at the end of life and can improve end of life outcomes. However, ACP in its current form assumes that people have agency and choice at the end of life. This is not the case for people who are homeless. Working with Tapu Atawhai/Auckland City Mission, the aim of this study is to explore the preferences, priorities, values and beliefs about death and dying in the homelessness community in order to develop a modified ACP document which is aligned with the needs of the community addressing preferences for place of care and dying, advocacy and legacy. We will also develop resources to support ACM staff with the skills, knowledge and confidence in having conversations about death, dying and advance care planning.

Funded by: Goodfellow Foundation’s Douglas Goodfellow Primary Healthcare Research Fund

Infections cause a high health burden worldwide, and Māori and Pacific peoples represent disproportional high rates in New Zealand. Vaccination is an effective prevention measure for life threatening and debilitating infectious diseases; however, many infectious diseases still await an effective vaccine. Mucosal vaccination holds promise in inducing local immunity that prevent the intruding pathogens from entering the host. We have developed PilVax, a novel mucosal vaccine platform using the pilus (fimbriae) structure of Group A Streptococcus (GAS) as a peptide carrier, and the food-grade bacterium Lactococcus lactis as a naturally adjuvanting vehicle. Previous results demonstrated that the stabilised and amplified antigens integrated in the PilVax construct can elicit desirable immune responses in mice. The aim of this project is to investigate the feasibility of using the PilVax platform to develop mucosal vaccines against respiratory syncytial virus (RSV) infection, a disease that causes high burdens, has significant unmet needs, and signals health inequity. In this proposal we will trial new designs of PilVax vaccination that can deliver multiple antigens and use animal infection models to demonstrate that these new designs can enhance immunisation efficiency and broaden vaccine coverage. This research will expand the versatility of PilVax, which holds promise to offer an inexpensive, safe and effective strategy for infectious disease control.

The popularity of a class of drugs known as GLP-1 agonists is rapidly growing due to their off-label use as weight loss medications. However, current recommendations advise that the use of such medications should be avoided during pregnancy due to potential side effects. As is also observed globally, a high proportion of pregnancies in New Zealand are unplanned (>40%). Further, almost 60% of women of reproductive age are either overweight or obese. A limitation of the experimental data to date is that it has been undertaken in the setting of normal pregnancies. However, pregnancies characterised by maternal overweight/obesity carry significant risks for both mother and infant including gestational diabetes and increased obesity and type 2 diabetes in the children. As such, the use of GLP-1 agonists before and during these pregnancies may actually represent a beneficial trade-off and improve pregnancy outcomes with reduced obesity. However, this has yet to be examined in a preclinical setting. We will use our validated animal model of maternal obesity to investigate the potential differential effects of GLP-agonists on maternal and infant outcomes in normal and obese pregnancies. This work addresses an important knowledge gap and such pre-clinical studies are essential to further our understanding of the potential risks and beneficial trade-offs of such treatment approaches in the setting of compromised pregnancies.

Approximately 70 babies born each year in New Zealand will develop brain injury because of oxygen deprivation during birth, which may lead to death or severe lifelong disability. The emotional toll on survivors and families is devastating, and the financial and socio-economic costs are immense, with each case costing New Zealand ~$36-56 million across a lifetime. Diabetes and high blood glucose levels during pregnancy increase the risk of oxygen deprivation. Less is known about the dangers of high glucose during birth itself, but our preliminary work shows that it impairs a baby’s ability to tolerate oxygen deprivation and worsens brain injury. This research will utilise a well-characterised, clinically relevant sheep model of brain injury during birth to help understand these dangers. The findings may suggest that a simple, immediately available intervention including tighter glucose control and a low threshold of escalation to expedited delivery in mothers with diabetes may significantly reduce the risk of severe oxygen deprivation and long-term neurodevelopmental disability. By making birth safer, this research will improve quality of life for mothers, children, and families with greater numbers of infants surviving to become contributing members of society and may bring substantial economic benefits to New Zealand’s health care system.

Swallowing difficulties are common in patients in intensive care units (ICUs) for a combination of reasons including their underlying condition, prolonged intubation, deconditioning and the multiple medical / surgical / pharmaceutical interventions received. Swallowing difficulties come with risks of secondary complications that can be life threatening and significantly prolong hospital stays, increase health costs and increase burden of care. Yet currently there are very few evidence-based interventions for swallowing difficulties in the ICU. In addition, many ICUs across New Zealand do not have access to adequate speech-language therapy support to provide intensive therapy. Expiratory muscle strength training (EMST) has been shown to improve swallowing and cough function in neurological populations. In a complex ICU population, where patients are weak and deconditioned, EMST may have merit. It does not require specialist staff to perform and can be done independently or with family support. In this randomised control trial, we will explore the effects of EMST in patients with intensive care unit-acquired weakness and swallowing difficulties. Patients will be randomised to EMST or standard care and assessed pre-treatment, 1 month and 3 months post-treatment. This easy-to-use and cost-effective device, if effective, will support equitable New Zealand health outcomes irrespective of locality.

Despite safe and effective surgical treatments, lens cataract is still the leading cause of blindness in the world today. This is in part because researchers do not completely understand how the lens maintains its transparent and refractive properties over many decades of life. Research by our laboratory has shown that in the absence of a blood supply the lens generates a circulating flux of water that maintains lens functionality. They have proposed these water fluxes are a target for the development of novel medical therapies to treat cataract. The water flow in the lens is mediated by several different water channels from the Aquaporin (AQP) family of proteins, which are critical to the maintenance of lens transparency. Recently, we have identified an additional water channel, AQP3, in the lens. Unlike the other lens AQPs, AQP3 has unique properties that implicate it in the transport of hydrogen peroxide, a known oxidative stress that has been linked to the initiation of cataract. Hence, by studying AQP3, we will determine not only the role played by AQP3 in the regulation of oxidative stress in the lens, but whether it is a potential target for the development of novel anti-cataract therapies.

Each year in New Zealand, 1500 women have a Caesarean section after the cervix is fully open. Caesarean at this time is more difficult because the baby's head is low in the pelvis. It is associated with increased injuries to mother and baby, including tearing of the uterus into the cervix and nearby organs, excessive blood loss, and injury to the baby's head and brain. These are serious injuries with potential long-term consequences and therefore costs to whanau and to the health system. The Fetal Pillow is a disposable silicon balloon, costing $615, placed in the vagina to elevate the baby's head, to reduce injuries to the mother and baby. Many doctors started to use the device without evidence that it works. In 2023 the original industry-funded trial was retracted due to integrity concerns. There remains a 60 women industry-funded trial supporting the device, and a number of retrospective studies (including one from Auckland) which mostly suggest the device is not useful. We plan to provide the first large, well designed, industry-independent, double-blinded randomised controlled trial evidence to determine whether the Fetal Pillow reduces maternal and neonatal injuries. In August 2023, the BEAD (Fetal Pillow) feasibility study began, which has recruited 55 women in 6 months. We are now applying for funding to complete recruitment of 400 women to this trial.

The incidence of in situ (non-invasive) breast lesions has increased in many countries after the introduction of population-based breast screening programmes. Ductal carcinoma in situ, the most common in situ lesion, now accounts for 20-25% of screen-detected cancer cases. These lesions may confer an increased risk of subsequent invasive cancer and therefore are treated extensively, putting a substantial burden on individual women, whānau and the health care system. Yet, little is known about their long-term outcomes in New Zealand women. Findings from overseas research may not be directly applicable to the ethnically diverse population in New Zealand, particularly for wāhine Māori and Pasifika women. We will fill this important gap in knowledge by linking individual patient data from a range of national data sources including breast screening data from BreastScreen Aotearoa and Te Rēhita Mate Ūtaetae (Breast Cancer Foundation National Register). The findings will guide clinical practice and help drive progress toward equitable cancer care.

Type 2 diabetes is a growing epidemic with over 300,000 diagnosed in New Zealand, and many more people estimated to be pre-diabetic. Diabetes damages the working cells of the heart leading to weakened contraction and poor heart function. Our research group has ethical approval to obtain tiny muscle samples from the hearts of consenting patients undergoing routine surgery. We have recently shown that heart muscles from diabetic patients do not contract as well as those from non-diabetics, and that the supply of mitochondrial energy that fuels contraction is impaired. This research project aims to use a new tissue culture system to monitor the contractile performance of isolated muscles over several weeks while optimising the metabolic fuel (glucose, fats, ketones) supplied to the muscle. We will utilise a novel muscle culture system (MyoDish) that is the first of its kind in New Zealand. The MyoDish will enable us to monitor beating muscle for periods of days-weeks. This allows us sufficient time to manipulate the metabolic fuel supplied during culture to determine whether optimising energy supply can "rescue" the contractile performance of muscles from diabetic patients. Results of our study will better inform management of diabetic heart disease, and improve patient outcomes.

Endometrial Cancer (EC; cancer of the uterus or womb) is a significant health and equity issue in Aotearoa. Pacific women have one of the highest incidence rates in the world, and it is rising extremely rapidly, with EC now being the biggest contributor to the life expectancy gap for Pacific women. There are also inequities for Māori women in both EC incidence and mortality. Potential drivers of EC include obesity, diabetes and menopausal status. More recently, studies have indicated links between vaginal and endometrial microbial communities (microbiome) and EC. In the US an anaerobic bacteria (bacteria which grows without oxygen), Porphyromonas somerae has been found to be associated with EC. The US lead author is collaborating with us to examine whether this bacteria can be detected, alongside changes in pH, on vaginal swabs and endometrial samples in a large and diverse population in Aotearoa; Māori, Pacific and non-Māori non-Pacific women. We will also examine the broader microbiome to see if there are differences for Aotearoa or between groups. Confirming a microbiome biomarker for EC raises the possibility of a minimally invasive screening test (vaginal self-test) in the future, with the ultimate aim of addressing EC inequities.

Each year around 8% of all Kiwi babies are born preterm. These vulnerable infants are at significant risk of life-long disabilities such as learning problems, reduced IQ, and behavioural difficulties, due to brain injury and impaired development. Exposure of the baby to oxygen deprivation in the womb or during birth is a major cause of brain injury. Currently, there are no brain protection treatments available for these infants. Preterm babies only show subtle clinical signs and brain injury can take days to diagnose. To realistically reduce brain damage in preterm infants, we need treatments that can be given even after a very long delay after birth. This preclinical study will examine if treatment with a clinically available drug (Exenatide) starting with a delay of multiple days after a period of oxygen deprivation can treat ongoing inflammation and promote the repair of the preterm brain. The findings from this study will provide crucial evidence for future clinical studies with the potential to reduce disabilities and improve outcomes of preterm infants.

Everyone with a life-limiting condition, their family and whānau, should have access to the best possible palliative care. For clients under palliative care, if medicines can no longer be taken orally, they are injected via a syringe in a portable pump over 24 hours. For every medicine contained within the 24-hour syringe, a corresponding ‘as required’ syringe is prepared for breakthrough pain or worsening symptoms. These syringes may be needed in a hurry at any time, and a ready supply of syringes has the potential to reduce admissions to hospital for symptom management. The syringes are often compounded using aseptic techniques in community pharmacies, but due to a lack of sterility and stability data, are assigned a conservative three-day expiry. This means the family must return to the pharmacy every three days to collect a new supply of medication, and any unused syringes are disposed of as pharmaceutical waste. This study will determine the stability of the most commonly used medicines in these ‘as required’ syringes, with a view to extend the expiry date where possible. A parallel study will determine the sterility of these syringes. In addition to reducing waste, extending the expiry date of these medicines will reduce the burden of families, giving them more time to spend with their loved ones.

Funded by: Douglas Goodfellow Primary Healthcare Research Fund

We are studying the efficacy and safety of Mifepristone to increase the rate of spontaneous labour in people who have undergone a prior caesarean birth. People who plan a Vaginal Birth After Caesarean (VBAC) ideally await spontaneous labour. Induction of labour increases the risk of repeat caesarean birth and the chance of complications. We have limited options to offer people wishing for VBAC. Prostaglandins, the most commonly used cervical preparation agents, are contraindicated in women with a prior caesarean. Oxytocin is an alternative. However, it requires an intravenous infusion, causes contractions and continuous cardiotocograph (CTG) monitoring is required when patients are receiving this medication. Oxytocin use is associated with a higher rate of unplanned repeat caesarean birth and labour complications including uterine rupture. Mifepristone blocks progesterone receptors causing cervical softening without significant uterine contractions. This mimics the process people undergo prior to labour. We will assess the use of Mifepristone to increase the rate of spontaneous labour in people with a prior caesarean birth by performing a double blinded randomised controlled trial. Participants are allocated to receive either a single dose of mifepristone or a placebo. The trial is patient-centred, with study visits occurring at the site of their choice, including their home. This approach is aimed at reducing barriers to access healthcare and trial participation.

Current approaches to managing postoperative pain after abdominal surgery rely on opioids. Opioids provide strong pain relief but have negative side effects. Local anaesthetic agents, such as lignocaine, work by "numbing" the nerves, and are being increasingly used worldwide instead of opioids. We have been studying the benefits of administering local anaesthetic into the abdominal cavity after surgery in patients for over ten years. We have developed an implantable device which is placed into the abdominal cavity at the time of surgery and immediately provides continuous delivery of lignocaine. This device has been designed with the specific goal of improving pain control following abdominal surgery. The device can be easily removed at any time. The device has been developed with DEC Pharmaceuticals, a Hamilton-based MedTech company. We have demonstrated the safety of this device in a sheep model. We are planning to conduct a Phase 1 study of our implant with ten participants who are undergoing colon surgery. The aim of this Phase 1 study is to demonstrate that this device is safe in humans. After this, we aim to demonstrate that the device is effective in reducing pain, by conducting further studies.

Funded by: Kelliher Charitable Trust

Parkinson's disease is a progressive neurological disorder affecting cognition and movement. It occurs when neurons in the brain that control these functions die or become damaged. The cause of neuronal loss is poorly understood, but the build-up of a pathological protein called α-synuclein is the leading hypothesis. α-synuclein can be cleared from the brain through various mechanisms, including the recently identified meningeal lymphatic system. This system sits in the borders surrounding the brain and functions as a drainage pipe to remove waste matter arising from the brain. In Parkinson’s disease, this system becomes dysfunctional, or “clogged”, which contributes to the build-up of harmful proteins. The cause(s) of lymphatic dysfunction in Parkinson’s disease are unknown. We will investigate the mechanisms underlying the “clogging” of these brain drains by studying the effects of α-synuclein—the major pathological protein in Parkinson's disease—on the lymphatic system using mouse models, human cell cultures, and brain border tissues donated by individuals with Parkinson's disease. Understanding how the lymphatic system is affected in Parkinson's disease could lead to new treatments targeting this system. Similar to clearing a blocked drain, restoration of lymphatic function could have significant benefits in promoting waste removal and associated cognitive benefits for Parkinson’s disease.

Fever is the most common reason children < 2 years of age are taken to emergency departments. International guidelines recommend that fever-reducing medications should only be used for relief of discomfort, rather than solely for lowering temperature. Paracetamol and ibuprofen are the two most widely prescribed and used over-the- counter medications for fever and pain in children, but the extent to which these medications improve discomfort in febrile children is unknown. It is unthinkable that there remains a knowledge gap regarding the appropriate use of paracetamol and ibuprofen for treatment of fever-related discomfort, given their universal use for fever and pain in young children. The Paracetamol and Ibuprofen in Kids Intervention (PIKI) Study ('Piki' is Te Reo Māori for 'to climb', 'to support'), will compare the efficacy and safety of paracetamol vs. ibuprofen for relief of discomfort in febrile children < 2 years of age in the emergency department.

Antibody-drug conjugates (ADCs) are a new and rapidly growing type of cancer treatment. ADCs use the selectivity of an antibody to deliver a drug directly to cancer cells, with the goal of avoiding the normal tissue toxicity which is often caused by chemotherapy. In this project we will prepare new versions of a type of drug that has been the focus of some recent ADCs developed for treating breast cancer. These new versions of the drugs have the right chemical properties to address current limitations and so make even better and more effective ADCs.

Multimorbidity (MM), having two or more long term conditions, affects one in four New Zealanders. The prevalence is highest for Māori, Pacific and older people, contributing to reduced quality-of-life and life expectancy. MM co-occurs in those at high CVD risk, yet NZ CVD risk management guidelines provide negligible advice about MM to guide GP-patient decision making. An existing research collaboration has curated a large deidentified dataset of adult patients enrolled in ProCare PHO, linked with national hospitalisation, pharmaceutical dispensing and regional laboratory data, and are investigating how well current NZ risk algorithms perform in the presence of MM. However, several conditions (gout, bundle branch block, polycystic ovarian syndrome, endometriosis, chronic migraine, hypertensive disorders of pregnancy, and gestational diabetes), which are strongly associated with increased CVD risk, are not captured by the NZ MM index, M3. We plan to replicate our M3-associated long term condition methodology to describe the prevalence of these conditions in GP records, investigate their impact on 5-year CVD hospitalisations and deaths, whether these conditions influence GP management of CVD risk and whether there are equity gaps by age, gender, ethnicity and deprivation.

Prostate cancer is the most common cancer to affect men in Aotearoa New Zealand, with an estimated 4,000 new cases a year. Men with high risk localised prostate cancer, are at greater risk of the cancer returning after their initial treatment, and we are continuing to explore ways to improve their outcomes. One area of interest is the use of radiotherapy targeting both the prostate and pelvic nodes at the initial treatment. Lymph node spread is common in men with high-risk prostate cancer, but it is often difficult to detect on scans. Recent studies have shown that by treating both the prostate and pelvic lymph nodes, we can reduce the risk of the cancer returning. In addition, with improvements in radiotherapy technology, we can now deliver this treatment safely. Prostate radiotherapy is typically delivered over 4 weeks (20 treatments). More recently, there has been shift to deliver radiotherapy over 5 treatments using an approach of stereotactic body radiotherapy (SBRT). Here, by applying extreme precision, a highly ablative dose per treatment is delivered to the prostate, and early data shows this approach to be safe. It is unclear whether SBRT can delivered safely and more effectively when treating both the prostate and pelvic nodes, and this PACE-NODES randomised study will provide further insight.

Liquid drugs, such as vaccines or insulin, can be delivered through the skin without a needle using ‘needle-free jet injection’. In this approach, the drug itself is formed into a hair-thin, high-speed jet that can break through the skin and into the underlying tissue. Removing the needle avoids the burden of infectious sharps waste and needle-phobia - which affects over 50% of children. Despite the benefits, needle-free jet injection has yet to be broadly successful in replacing needles. A significant barrier to uptake is that jet injection studies continue to report failed injections, inconsistent delivery volumes, and/or variable pain or comfort scores from patients. How the injector is pressed against the skin determines how successful and comfortable the injection will be, however, we still do not understand the best way to stretch or contact the skin before an injection. By building a new system to control skin tension and the jet-induced movement of the skin we will investigate how these affect jet penetration and fluid delivery. This will inform the design of injectors, or could lead to new techniques, that improve the ease and consistency of jet injection - allowing us to realise the broad benefits of avoiding needles.

Asthma is the most common illness of childhood, and the leading cause of emergency department (ED) visits. Māori and Pacific children are more frequently affected, and three times more likely to require hospitalisation. Preschool wheeze is treated similarly to asthma in older children, including 3-days of oral steroid medication for moderate or severe episodes. However, recent evidence suggests that wheeze in preschoolers is a short-lived illness, meaning these children may require only 1-day of oral steroid. Thus, in the STeroids in preschool Asthma Reduction (STAR) Study, we will compare respiratory outcomes in wheezy preschoolers treated with 1- versus 3-days of oral steroid. If this study shows that outcomes are the same for children who receive the shorter course, their treatment will be simplified, and their risk of steroid-related side-effects greatly reduced. This will be especially relevant for preschoolers who suffer recurrent wheezy episodes and receive several courses of steroid each year. Furthermore, this study has potential to improve equity of care for wheezy preschoolers, as if a single dose of oral steroid is as effective as a 3-day course, there will be no need for further doses following discharge.

Our immune system must be able to distinguish between components of our own bodies (self) which it must ignore and bacteria or viruses (non-self) which it is designed to destroy. Organ transplants are rejected because the recipient’s immune system recognises the transplant as non-self and attacks it. Because it is derived half from dad, the placenta/fetus are nature’s only transplant. We don’t understand how nature tricks the maternal immune system into allowing the fetal transplant to survive during pregnancy but this process goes wrong in a life-threatening disease called preeclampsia, which is found only in pregnant women. We believe that tiny packages called extracellular vesicles, which are pushed out of the placenta into mum’s blood are the key to how the fetus controls its mother’s immune system. We are investigating which immune cells interact with placental extracellular vesicles and how that interaction alters the maternal immune system in normal and preeclamptic pregnancies. We expect pregnancies to be safe but approximately 5% of pregnant women develop preeclampsia which has both immediate and long-term consequences for mother and babe. This research will give us a better understanding of how the immune system is controlled in pregnancy and what goes wrong in preeclampsia. These are the first steps towards developing new treatments for preeclampsia.

Mycophenolate mofetil (MMF) is an immunosuppressant drug which targets an enzyme in white blood cells, inosine-5′-monophosphate dehydrogenase (IMPDH). It can be used to treat patients with the autoimmune disease systemic lupus erythematosus (SLE) who develop potentially life-threatening kidney damage (lupus nephritis). This study aims to understand how differences in IMPDH between SLE patients affect how well MMF suppresses its activity, and how this changes over time. We will also investigate the way MMF enters each person’s immune cells, as well as inherited differences between patients that might affect outcomes both for MMF and for an alternative drug used to treat lupus nephritis (cyclophosphamide). Understanding these factors could help doctors to predict which patients are likely to benefit from MMF therapy, and which ones are more likely to benefit from cyclophosphamide instead.

Children who are born to mothers with overweight or obesity are more likely to develop problems with their weight, and metabolic diseases such as diabetes and cardiovascular disease as they grow up. This is because they are born with alterations to how their body's metabolism works. As over half of the children born in New Zealand, will have a mother with greater weight, this is important. Unfortunately, we don't have any effective treatments to reduce the risk for these children once they are born. We also don't know if Dad's health is as important as Mum's. This study will use a high-fat high-sugar, Western junk food diet, in rats, to find out the relative importance of the mother and the father's diet and body fatness, and also find out whether a fish oil treatment given to the offspring during childhood can prevent weight and metabolic problems from developing as they grow up. This could lead to better health advice for both men and women who wish to become parents, and to a rescue treatment, to protect children born at risk of weight problems.

Delirium is the most common serious postoperative complication, occurring in an estimated one in four older adults undergoing major surgery. Delirium causes significant distress to patients, whānau and hospital staff, and is associated with prolonged hospital stays, physical decline and progression to dementia-like illnesses. A population-based study in NZ shows that Māori patients are more likely to experience delirium at a much younger age after surgery. This study compares 'light' to 'deep' anaesthesia during surgery using widely available brain monitors, to see if 'light' general anaesthesia could reduce rates of postoperative delirium. Previous literature suggests that targeting 'light' anaesthesia may reduce delirium rates by up to 25%. Over 10% of adults aged 70 years and over undergo surgery each year and this simple, cheap, and readily available treatment could reduce disability, preserve brain health and well-being of many older adults in NZ and worldwide. This could also save millions of healthcare dollars.

Regulatory T cells (Tregs) are a specific subset of immune cells that play a critical role in balancing the immune response. We do not understand the dynamics of how these cells evolve in early life. Through experiments on blood and stool samples of term and preterm babies, we explore how short chain fatty acids, metabolic products produced by harmless bacteria in the gut, influence the development of Tregs. Our investigations will characterise how Tregs interact with other immune cells and how their function can be positively influenced. The results will help fight immunological complications affecting newborn babies as well as allergies and autoimmune disorders in later life.

Our ability to move, to respond to reward and to see, are physiological and behavioural processes that involve the action of the signalling chemical dopamine in the brain. Dysfunction in dopamine and its pathways play a major role in neurological disorders including attention deficit hyperactivity disorder (ADHD). Around 5% of the New Zealand population has ADHD but only 1-2% are diagnosed; once correctly diagnosed, there are various ways to help a child with ADHD. We propose that in affected ADHD people the eye holds biological clues (biomarkers) that could guide a more precise objective diagnosis of the disease in children. We will test the hypothesis in an animal model where dopamine levels are high, using a combination of molecular and electrochemical techniques, biometric and retinal imaging assessment of the eye. Collectively, these findings will identify reliable biomarkers of dopamine dysfunction and determine how these pathways are compromised with disease. This information will provide a more effective assessment of ADHD, measurable non-invasively using biomarkers obtained during an eye test in children.

While regarded as “benign”, meningioma may have devastating consequences such as blindness, permanent weakness, and even death. A major problem with meningioma management is the difficulty in predicting which tumours may recur. Identifying improved ways of predicting which meningiomas are most likely to recur will allow closer follow-up and/or early additional therapy which may improve outcome. Presently, we do not know what the best means of assessing recurrence risk is. Advanced molecular testing and the “molecular-morphologic meningioma classification” has been reported to perform well. But it is expensive and has never been compared to more sophisticated and essentially “free” methods of stratifying risk such as our newly developed “Auckland meningioma score” which uses tumour grade, extent of resection, site, size, and ethnicity to assign recurrence risk. By comparing three risk stratification methods: the current post-operative meningioma risk stratification pathway, “Auckland meningioma score”, and the molecular-morphologic meningioma classification we aim to determine the best method of predicting meningioma recurrence risk. In doing so this study will provide a strong evidence base to determine the optimal risk stratification tool for patients undergoing meningioma resection in Auckland, allow best use of healthcare resources, and improve the quality of care following meningioma surgery.

Immunotherapy is the future of cancer care. By stimulating the patient’s immune cells to fight cancer cells, immunotherapy can cure cancer. Yet, sadly, this does not happen in most patients because the cancer sabotages their immunity. Two key saboteurs hired by cancers are enzymes called IDO1 and TDO. They produce a chemical called kynurenine that paralyses cancer-killing immune cells. To sensitise patients to curative immunotherapies, kynurenine needs to be stopped. Unfortunately, developing safe and effective drugs that will block IDO1 and TDO at the same time is proving harder than first anticipated. To get around these difficulties, we aim to block kynurenine production in a simpler and likely more effective way. We propose to inactivate an enigmatic enzyme called arylformamidase required by both IDO1 and TDO to make kynurenine. We have just generated promising results in ovarian cancer cells suggesting that arylformamidase is indeed the only gene producing kynurenine. In this research, we will confirm this finding in diverse cancer cell types and find out if arylformamidase is present in human tumours. This research has potential to establish arylformamidase as a target for drugs that can sensitise more cancer patients to life-saving immunotherapies.

There is no intervention to prevent or delay the onset of hearing loss, a condition that affects over 800,000 people in NZ. Our hearing is dependent on the auditory neurons located deep inside the organ of hearing, the cochlea. The health of auditory neurons is critically dependent on the delivery of nutrients and oxygen by blood vessels. However, the fine network of small blood vessels supporting these neurons has not been well researched. To fill this gap of knowledge, our collaborative research team will use a novel combination of 3D imaging techniques to enable the investigation of these small structures deep inside the cochlea. This research will inform us how tiny blood vessels surround auditory neurons and how they develop and change with age. This fundamental information will help us understand how auditory neurons may be affected by changes in blood flow following damage or surgical interventions. In the long term, this will help us develop new diagnostics and therapies to optimise the health of neurons in the cochlea, to prevent deterioration of hearing in people starting to experience hearing loss and to preserve nerve function in patients with cochlear implants.

In New Zealand, 70 babies a year develop brain injury due to the loss of oxygen or blood supply around the time of birth. This can lead to death or lifelong disability. The only treatment available for these babies is brain cooling, but nearly half of the babies that are treated will still develop brain injury. Treatments that can be used alongside brain cooling are urgently needed to improve the outcome for these babies. We have shown that there is unresolved inflammation in the brain, even after treatment with hypothermia. This inflammation likely contributes to brain injury and disability. Therefore, we propose that targeting this inflammation with Exendin-4 (a drug that has anti-inflammatory effects), after treatment with brain cooling will further reduce brain injury. This research will help provide crucial information as to how to improve care of these vulnerable babies, including how best to reduce brain damage and disability and improve the quality of life for these babies and their families.

Co-funded with Neurological Foundation of New Zealand.

Antimicrobial resistance (AMR) represents a global health threat to humanity. Since their introduction in the 1940s, antibiotics have been the cornerstone of modern medicine saving lives by being able to cure infectious diseases and to prevent infections in those that are immune compromised. With time has come an increase in the incidence of antibiotic-resistant bacteria, driven by inappropriate prescribing and the ability of bacteria to adapt to, and overcome, the action of antibiotics. Of particular concern, is the emergence of Gram-negative bacterial resistance in the clinic – with no new Gram-negative antibiotic having been discovered for decades, infections caused by these organisms can become essentially untreatable. A strategy for overcoming Gram-negative bacterial resistance is to identify adjuvant compounds that can 'rehabilitate' old antibiotics, restoring their effectiveness to aid in the fight against drug-resistant bacterial infections. This proof-of-principle study exploits our recently discovered family of non-toxic, bacterial membrane disrupting adjuvants to now prepare hybrids that combine antibiotic and adjuvant into a single molecule. We anticipate that the hybrid will exhibit growth inhibition activity towards otherwise resistant Gram-negative bacteria, cementing this as a strategy to expand the utility of disused legacy antibiotics and to provide alternative methods for combating antimicrobial resistance.

Preschool wheeze is a common cause of hospital admission of preschool-aged children worldwide and the most common cause in Australia and New Zealand. Current prevention strategies are ineffective and potentially harmful. Novel approaches are needed. OM-85 is an orally administered bacterial lysate that stimulates immune responses against viral infections and reduces the excessive inflammation of the respiratory mucosa associated with wheezing episodes. In placebo-controlled trials, OM-85 reduces recurrent respiratory infections in children and is well tolerated. Larger studies are required to evaluate whether OM-85 prevents wheeze-related hospitalisations. Children 1-5 years old with a history of wheeze and admitted to participating Australasian hospitals (seven in New Zealand) with a wheezy illness will be eligible. 2268 children will be enrolled and randomly assigned 1:1 to OM-85 or placebo. This trial will determine the efficacy of OM-85 for preventing hospitalisations in preschool-aged children with recurrent wheeze and assess the effect of OM-85 on subsequent recurrent wheeze events. End-user engagement from inception and detailed cost-effectiveness analysis will facilitate rapid translation of the findings into policy and improved health outcomes in Australasia and internationally.

Immunotherapy is a type of cancer treatment that helps direct our immune system to fight cancer. Unfortunately, only a small number of patients who receive immunotherapy will benefit. Patients that do respond to immunotherapy typically have large numbers of immune cells present within their tumour. This suggests that if we can recruit additional immune cells to the tumour, we can improve the effectiveness of cancer immunotherapy for more people. Many immunotherapies are also associated with autoimmune-related side effects that can vary in severity. The non-pathogenic anaerobic bacterium Clostridium sporogenes offers a unique solution for improving the tolerability and effectiveness of immunotherapy in more patients. Upon injection as inert spores, Clostridium sporogenes can germinate into active bacteria in particular regions of the tumour (necrosis), resulting in a tumour-specific bacterial infection. This research will investigate whether a strain of Clostridium sporogenes engineered to express an immunotherapy agent can 1) Provide specific and continuous delivery of immunotherapy from inside the tumour, minimising the potential side effects from intravenous delivery; 2) Recruit more immune cells to tumour tissue to make cancer immunotherapy more effective. If successful, this approach could produce meaningful results for a significant number of patients who do not respond to immunotherapy.

Chronic tinnitus is a debilitating condition affecting approximately 10% of the population and for which there are limited treatment options. The perception of auditory signals can be modulated by a neural network called the auditory gating system, which filters repeated irrelevant sounds. While our most recent studies have provided direct evidence of a dysfunctional gating system and a link between the brain reward system in an animal model of tinnitus, it is not clear what molecular changes are driving this. As dopamine neurotransmission is involved in both auditory gating and the reward system, this project will investigate the involvement of dopamine in tinnitus. Specifically, we will induce tinnitus in rats using acoustic trauma and confirm the animal’s perception of tinnitus using a well-established behavioural paradigm. We will then measure dopamine release in brain areas involved in auditory perception, auditory gating and reward using an advance technique called fast-scan cyclic voltammetry, and compare dopamine release between control, tinnitus positive and tinnitus negative animals. The results will contribute to a better understanding of tinnitus and inform further studies into developing effective treatments for tinnitus.

Funded by: Jean Cathie Fund for Tinnitus Research

Acute and critical illnesses such as sepsis, trauma, meningitis and acute pancreatitis, all show signs of widespread inflammation across the body. In severe cases, these lead to organ failure, which is the leading cause of death in intensive care units. Māori and Pasifika are more likely to develop acute and critical illness than others, with Māori that present to intensive care being on average ten years younger than non-Māori. Low oxygen levels in the gut and subsequent gut injury are known to be important contributors to poorer outcomes for these patients, yet there are no clinical strategies available to protect or treat the gut. Our project presents a genuine potential advance to address a treatment gap urgently needed in acute and critical patient care. Our approach will limit both the development and progression of low-oxygen gut injury caused and so is expected to see use as both a prevention and a treatment for acutely and critically ill patients. The work we perform will lay the foundation for future clinical trials to evaluate oxygen microbubbles in improving the clinical outcomes, including quality of life, from acute and critical illness.

Delivering a self-compassion intervention via a chatbot (conversational agent) is a novel approach for improving psychological health in adolescents with type 1 diabetes. Adolescents with type 1 diabetes are at higher risk for psychological disorders and life-threatening diabetic complications, factors that disproportionately affect Māori and Pacific youth. We plan to adapt a self-compassion chatbot (called COMPASS) for Māori and Pacific youth (Phase 1) and conduct a feasibility study (Phase 2) with 40 adolescents with type 1 diabetes aged 12-16 years in Auckland and Christchurch to test the usability and acceptability of COMPASS as well as test the methods and recruitment approach, in preparation for a subsequent multi-centred randomised controlled trial. We believe COMPASS could help to transform clinical diabetes care in Aotearoa.

Gonorrhoea is a sexually transmitted disease (STD) that, if remains untreated, can lead to complications such as infertility. There are an estimated 78-106 million new cases each year worldwide and New Zealand rates were reported as 100 per 100,000 population in 2017. Māori and Pacific People have significantly higher gonorrhoea rates compared to Europeans. The World Health Organisation (WHO) has declared the development of effective treatments against this bacterium a global priority. We propose to generate a vaccine against gonorrhoea using PilVax, our recently developed peptide carrier. PilVax uses the rigid scaffold of a bacterial pilus structure to stabilise and multimerise introduced peptides and small proteins to trigger strong mucosal immune responses. We will test four selected gonococcal vaccine targets and analyse immune responses in vaccinated mice. Furthermore, we will investigate if vaccinated mice are protected against infection with the bacterium Neisseria gonorrhoeae, the causative agent of gonorrhoea. An effective vaccine against this bacterium would not only prevent gonorrhoea, but also limit the spread of antimicrobial resistant strains.

In New Zealand, more than 300,000 people are currently diagnosed with diabetes and the burden falls disproportionately on Māori and Pacific Island populations, with 2.8-fold higher prevalence and mortality rate approaching 6 times that of non indigenous populations. Diabetic patients have increased risk of heart failure and the prevalence of subclinical heart dysfunction in type 2 diabetes is estimated to be as high as 75%. We have recently discovered that fructose sugar is a key instigator of cardiac damage in the diabetic heart, and our proof-of-principle studies have demonstrated that intervention to slow down fructose metabolism in the heart results in complete restoration of cardiac function. This study aims to provide robust pre-clinical data to demonstrate the potential for a novel fructokinase inhibitor to treat diabetic heart disease. This project has the potential to drive the re-purposing of an existing drug, already safety tested in the clinic, to accelerate a new therapy for diabetic heart disease - a condition which has dire consequences and for which there is currently no treatment available.

Approximately 70 babies born each year in New Zealand will develop brain injury because of oxygen deprivation during birth, which may lead to death or severe lifelong disability. Midwives and obstetricians play a key role in assessing this risk and determining whether it is safe for labour to continue. The main method used to assess whether babies have sufficient oxygen is foetal heart rate monitoring. Unfortunately, foetal heart rate monitoring is very imprecise, making it difficult to conclusively determine whether babies are healthy or not. This can lead to tragic outcomes for both babies and families but also contributes to many mothers receiving unnecessary caesarean sections. We believe that there are clues in the subtle fluctuations of foetal heart rate that will provide early warning when a baby is in trouble. This research will help midwives and obstetricians provide the best possible care to all mothers and babies, reducing both the risks of unnecessary caesarean sections to mothers and the risks of brain damage and disability to their babies. This will improve quality of life for mothers, children, and their families.

Infants, children and young people with serious illness and their families and whānau currently receive palliative care that is dependent on where they live, and the expertise, knowledge and skills of the clinicians caring for them. While there is a specialist children's palliative care service based in Auckland and a small number of clinicians with specialist training in other parts of the country (Wellington, Christchurch and Waikato), paediatric palliative care is primarily delivered by paediatric teams in regional centres. These clinicians strive to do their best for children and families but have variable skills and training in this area. There is significant interest from paediatric teams to develop knowledge and skills to deliver quality palliative care to children. Currently there is no formal Paediatric Palliative care education programme available in New Zealand. This project aims to explore paediatric clinician’s attitudes, knowledge and skills in caring for children with serious illness and palliative care needs and seeks to develop an evidence based and culturally safe education programme specific to the New Zealand context recognising care needs of both Māori and non-Māori tamariki and their whānau. The education programme hopes to develop local skills and knowledge in Paediatric Palliative Care, ensuring equitable care is provided to all children and whānau.

Antimicrobial resistance (AMR) arises when bacteria, fungi, parasites or viruses change over time and develop the ability to ward off the drugs designed to destroy them, making the treatment of infections difficult or even impossible. AMR is recognised as one of the leading threats to global health, currently resulting in about 2000 deaths daily, with fatalities predicted to skyrocket more than 10-fold within the next 30 years. In New Zealand, infections caused by multidrug-resistant microorganisms are increasing, with the overuse of antibiotics and travel from regions with higher AMR levels (like South-East Asia) exacerbating the problem. Our research will utilise a different approach to drug design, where two complementary antibiotics are linked together into a single molecule. This approach offers several potential advantages, including better potency and safety, and a reduced chance of generating resistance; there are now several candidates of this type in clinical trials. By linking two drugs from a newly approved regimen to treat multidrug-resistant tuberculosis, we have already been able to demonstrate superior antibacterial activity, including against resistant strains. Our study will optimise the design and physical properties of these “antibiotic hybrids”, aiming to develop a more effective and safer drug to treat severe bacterial infections.

In 2016, ACC funded the implementation of an innovative, national simulation-based team training programme for all public hospitals in Aotearoa - NetworkZ. The simulations are run in the actual workplace (in-situ), simulating real clinical challenges, and testing both the teams and the systems.
With NetworkZ, we have transformed the capacity for simulation-based training for hospital staff across all public hospitals, both rural and urban, providing a valuable avenue for preparing teams to deal with future challenges in healthcare. Alongside this team training, we have identified multiple potential threats to patient safety such as missing, faulty, or inadequate equipment; lack of common understanding of protocols such as response to massive bleeding or trauma team activation; and gaps in staff knowledge and training. Though many of these faults have been resolved, there remains an ongoing challenge in systematically learning from these threats and ensuring they are fixed and are no longer a potential cause of harm to patients. In this study, we aim to proactively identify underlying threats in the operating and emergency departments. We also aim to develop a national threat reporting system through an in-depth exploration of factors that facilitate or impede resolving these threats. It will improve the identification of threats (by standardised in-situ simulations) and resolving these potential threats to patients through a national approach to quality improvement.

This study examines why premature babies have a high risk of neurodevelopmental impairment in later life. We have shown experimentally that exposure to infection/inflammation can impair growth of the brain, consistent with clinical findings. We will test the central hypothesis that inflammation-induced opening of small channels in the brain (called hemichannels) is a key regulating event that triggers impairment of brain development. We will dissect the role of hemichannels using a newborn model of low dose injection of inflammatory molecules and treatment with connexin hemichannel blocking peptides. This new knowledge will underpin the development of new treatment strategies for infection-related brain damage.

Lignocaine infusions during and after surgery are increasingly popular to control pain, particularly in surgery for endometriosis, colorectal cancer and breast cancer. However, dosing is poorly defined and does not consider patient and surgical factors that may influence pharmacokinetics and clinical outcome. Current understanding of lignocaine pharmacokinetics (the relationship between dose and concentration) is inaccurate and outdated. Commonly used dosing regimens have resulted in plasma concentrations which may exceed the accepted toxic plasma concentration of 5µg/ml. The objective of this project is to develop robust pharmacokinetic model for lignocaine and its metabolite that will allow us to rationally adjust dose for different pain settings, populations, and over longer treatment durations without compromising patient safety. The study aims to characterise the pharmacokinetic profile of lignocaine and its primary active metabolite using population pharmacokinetic models. This is a prospective, observational, multicentre clinical study of 50 patients undergoing elective surgery within the Auckland region. Patients who are planned to receive intravenous lignocaine as part of their anaesthetic will be recruited. Patient and treatment factors and blood samples will be collected to develop a population pharmacokinetic model of lignocaine and its metabolite.

The End of Life Choice 2019 Act (the Act) comes into force in New Zealand on November 7, 2021. The Act provides a framework for people experiencing unbearable suffering from a terminal illness to have the option of requesting medical assistance to end their lives. The Act is likely to create many legal, ethical, clinical, and social ripples as it is implemented. This project has two aims. The first aim is to explore the experiences of health practitioners involved in assisted dying and allow them to reflect on their experiences. International studies have shown that participation in assisted dying has significant emotional and psychological effects on the involved practitioners. The second aim is to gain a more complete picture of the impacts of the Act by exploring the perspectives of whānau/family of assisted dying. This project has the potential to uncover knowledge and service gaps in the provision of the Act, along with understanding the emotional and other impacts of assisted dying on health practitioners and whānau/families. A knowledge translation plan will be developed to expand knowledge and capacities amongst key stakeholders and recommend changes in practice informed by the project findings.

Diabetes is one of the most common health problems in New Zealand affecting over 250,000 New Zealanders. It is associated with several complications one of which is diabetic retinopathy (DR), a chronic disease that can lead to vision loss. While there are a range of therapies currently available, these only treat late-stage DR signs without slowing the disease progression. Previous work done in our lab and by others have identified a new disease mechanism, the inflammasome pathway, that plays a role in the development and progression of DR. Furthermore, we have shown using several disease models that blocking this pathway using our anti-inflammasome drugs can prevent the development of DR. In the proposed study, we hope to use human donor eye tissues and blood samples to better understand how the inflammasome contributes to DR progression and to determine the best time to treat patients to prevent or reverse disease signs.

As NZ moves through the COVID-19 crisis to recovery, the long-term impact of the pandemic is of pressing concern. The pandemic has involved stressful challenges that continue to pose a threat to health and well-being. The scientific community has documented the health costs of the pandemic but has overlooked the family processes that may undermine or protect children’s health and well-being during this challenging time. The current research answers an urgent call to identify ways to address the costs of pandemic-related family disruptions to children’s health and well-being. Leveraging an existing family study, we will track the health and well-being of NZ families prior to the pandemic, during the Level 4 lockdown, and two years into the pandemic to identify the family risk processes (inter-parental conflict, poor parenting) that increase the risk of detrimental health and well-being outcomes for children. We will also identify the family resilience processes (family cohesion, co-operative coparenting) that buffer the health and wellbeing costs of the pandemic. The results will offer valuable insight into how to cultivate family resilience in the face of stress and insecurity, thereby improving the health and quality of life of NZ families and their children.

Despite safe and effective surgical treatments, lens cataract is still the leading cause of blindness in the world today. This is in part because researchers do not completely understand how the lens maintains its transparent and refractive properties over many decades of life. Research by our laboratory has shown that in the absence of a blood supply the lens generates a circulating flux of water that maintains lens functionality. They have proposed these water fluxes are a target for the development of novel medical therapies to treat cataract. The water flows in the lens are mediated by several different water channels from the Aquaporin (AQP) family of proteins, which are critical to the maintenance of lens transparency. Recently, we have identified an additional water channel, AQP3, in the lens. Unlike the other lens AQPs, AQP3 has unique properties that implicate it in the removal of hydrogen peroxide, a known oxidative stress that has been linked to the initiation of cataract. Hence, by studying AQP3, we will determine not only the role of AQP3 in the lens, but whether it is a potential target for the development of novel anti-cataract therapies.

Type 2 diabetes (T2D) is one of the largest and fastest growing health issues within New Zealand and is closely linked with the development and progression of cardiovascular diseases, including cardiac dysfunction, arrhythmias and heart failure. Our study focuses on the calcium cycling changes that occur in the heart’s contractile cells, cardiomyocytes. Each heart beat is triggered by coordinated calcium release within cardiomyocytes. Clearance of calcium within cardiomyocytes between beats (diastole) is equally important for proper relaxation to enable refilling of the heart. When calcium release occurs between beats this is known as ‘diastolic calcium leak’. Our recent research has revealed that atrial tissue from diabetic patients have increased diastolic calcium leak and contract more weakly than tissue from non-diabetic patients. These observations warrant further investigation since diastolic calcium leak in animal models of heart disease has been shown to drive progression to heart failure, trigger fatal cardiac arrhythmias, promote muscle damage and decrease exercise capacity. The overall aim of this project is to identify and target cellular and molecular triggers that promote diastolic calcium leak in human atrial tissue from diabetic and non-diabetic patients. This information will be invaluable in identifying strategies to protect the hearts of diabetics.

Improved treatments mean more people are surviving events such as heart attacks, and are then living with heart disease. Recurrent events for these people are common, with nearly 30% dying or being readmitted to hospital for related causes within one year of their first heart attack. Despite being a leading cause of death for women, historically there has been significant under-representation of women in heart disease research studies and the evidence base for therapies is less in women than it is for men. In this study of 800 women admitted to New Zealand hospitals with a first-time heart attack, we will measure a number of heart biomarkers (including genetic markers of heart disease risk), as well as the known clinical and environmental cardiovascular risk factors such as nutrition, stress, and physical activity. This will help us to better understand how heart attacks manifest differently in women compared with men, and to identify risk markers for subsequent events that are specific to women, leading to more personalised and better targeted treatments and more equitable health outcomes for women with heart disease in New Zealand.

Group A Streptococcus (GAS) is a human pathogen responsible for a number of diseases, including acute rheumatic fever (ARF) and rheumatic heart disease (RHD). These diseases are the cause of significant mortality and morbidity globally, with Māori and Pacific children in New Zealand amongst the most heavily impacted. GAS can become internalised inside host epithelial cells, forming intracellular reservoirs that allow it to evade the host immune system and drug treatment. This internalisation is associated with treatment failure and recurring GAS infection. The current antibiotics (e.g. amoxicillin) used to treat GAS infection, fail to penetrate host epithelial cells and new cell permeable treatments are desperately needed. Some antimicrobial peptides (AMPs) have recently been identified to penetrate human cells without significant toxic effects, but their usefulness is often limited by poor half-life. Peptide stapling is a modern approach to improve the biological stability of AMPs and importantly, is established to enhance mammalian cell penetration. However, the ability of stapled AMPs to eradicate internalised bacteria (e.g. GAS) is yet to be investigated. Using a novel and improved peptide stapling technique recently developed by the lead investigator, stapled AMPs will be prepared and investigated as new treatment strategies for intracellular GAS infections.

Each year 25,000 people in New Zealand are diagnosed with cancer, with a large number undergoing surgical treatment under anaesthesia. Alarmingly, early evidence suggests that the type of anaesthetic drugs used during surgery can affect cancer spread, patient survival and the risk of experiencing long-term pain after surgery. Recent studies show that traditional inhaled (volatile) anaesthesia may have a negative effect on the body's defence systems, resulting in worse outcomes after cancer surgery. Early evidence suggests that the more recent alternative anaesthetic drugs propofol (total intravenous anaesthesia) and local anaesthetic lignocaine infusion may protect the immune system, thereby reducing cancer metastasis, improving patient survival and decreasing chronic pain after surgery. We are participating in an international trial to identify if widely used anaesthesia drugs can improve outcomes in patients undergoing surgery for bowel or lung cancer. Bowel cancer and lung cancer are the two highest causes of cancer death in New Zealand, with almost 3000 New Zealanders dying from these diseases each year. We believe that this study has the potential to drastically improve patient well-being and population health for a large number of New Zealanders.

In New Zealand and around the world, perinatal oxygen deprivation remains a major cause of neonatal death and lifelong disabilities such as cerebral palsy. These outcomes are devastating for the individual, families and caretakers, and place a significant burden on our finite healthcare and educational resources. Therapeutic hypothermia, mild brain cooling, was developed in New Zealand and is now standard treatment for perinatal brain damage from oxygen deprivation, to improve infant survival without disability. However, hypothermic protection is partial such that nearly half of infants either still die or develop disabilities, despite brain cooling. Thus, new strategies that can further improve neurological outcomes are critical. Recent evidence suggests that recombinant erythropoietin, a pleiotropic growth factor, can support survival of injured brain cells, and help promote repair of the newborn brain after oxygen deprivation. It is not known if recombinant erythropoietin can improve outcomes after hypothermia. This research project will use the same clinically-relevant model of oxygen deprivation in the developing brain that helped establish therapeutic hypothermia, and tests whether giving recombinant erythropoietin after therapeutic hypothermia is better than cerebral cooling alone. This will provide critical information that will guide future clinical trials.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $7,768. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Prostate cancer is the most common cancer affecting men in New Zealand. Traditionally prostate cancer was treated with radiation over a period of 7-8 weeks. The impact of prolonged treatment in terms of increased hospital visits and its effect on the budget is quite significant. Recent evidences have shown that it can be effectively treated over 4 weeks safely and has thus been adopted as the standard of care. PACE C aims to reduce it further to just five fractions. This would allow the patients to return to normal life faster and bring down the economic and psychological burden. Moreover, the positive effect on the radiotherapy services nationwide is substantial. The reduction in the treatment duration results in an increased capacity for the radiation units thereby allowing us to treat more patients in any given time and as such faster access to healthcare by all. Ultimately, this provides easy access for all to the best services, in a timely manner to improve overall cancer outcomes. Despite a large body of evidence for SBRT (Stereotactic Body Radiotherapy) in prostate, PACE C is the first randomised trial comparing these two radiation schedules and its results can change the present standard of care.

Aotearoa New Zealand is in a unique position internationally due to our low community exposure to the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Hence we can expect that very few dialysis or kidney transplant recipients will have immunity to COVID-19. Vaccination is expected to be undertaken in 2021. Dialysis and kidney transplant recipients are often less able to mount an immune response to vaccination. In addition, vaccination can stimulate anti HLA antibodies and cause acute antibody mediated rejection in transplant recipients and reduce the likelihood of acceptable transplant matches for patients on dialysis waiting for a transplant. We plan to measure the serological response to the COVID-19 vaccination in patients on dialysis and after kidney transplant in order to determine if these patient groups have a lower response to vaccination. Additionally we will identify whether patients awaiting kidney transplantation develop new anti HLA antibodies after vaccination.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $11,620.

Acute leukaemia and myelodysplasia are the cause of most bone marrow transplants worldwide. This study aims to prove that a drug called cyclophosphamide works better than current standard of care at reducing the side effects and preventing graft-versus-host-disease (GVHD) in BMT patients. Currently, 40% of bone marrow transplant patients develop GVHD and 5-10% die within a year of transplant. While their initial disease is cured, many surviving patients suffer with the terrible effects of this painful, debilitating disease. The BM12 CAST study is a randomised clinical trial conducted in the hospital setting. It is the only study of its kind testing this new treatment to reduce side-effects and improve the quality of life for post-transplant patients and positive results will have an important impact on international treatment practice.

Cancer cells use DNA repair mechanisms to escape the full effects of cytotoxic chemotherapy and radiotherapy. Our recent discovery of a new drug, SN39536, that inhibits a key repair enzyme, DNA-dependent protein kinase (DNA-PK), provides a new tool to potentiate cancer treatment with both modalities. This DNA-PK inhibitor could also be used in patients whose tumours have defects in the DNA repair genes, a very common feature of cancer cells that results in metastasis and therapy resistance. We are seeking to identify which particular tumour mutations will combine with the drug to kill the tumour cells. We will use a gene-editing approach to individually inactivate every gene involved in DNA repair and then monitor the effect of SN39536 alone, or in combination with chemotherapy or another DNA repair inhibitor. The identification of effective drug-mutation combinations will provide a path to clinical use of SN39536 in cancer patients whose tumours harbour these defined mutations. This approach is likely to have reduced side effects compared to conventional chemotherapy or radiotherapy.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $12,702. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Human heart failure is the inability of the heart to pump enough blood to meet the energetic demands of an active lifestyle. This condition results from cardiac muscle cells losing their ability to generate force. This is a serious health condition and a major cause of death in New Zealanders. In this research, we will investigate a novel pacemakers ability to reverse remodel the pathological changes that damage the electrical connections responsible for signalling muscle cell shortening that generates force. In particular, we are interested in characterising the changes in collagen remodelling that is responsible for damaging these electrical connections, a finding we identified in previous research supported by the Auckland Medical Research Foundation. Moreover, we will identify which molecules interact with collagen VI, how they change in heart failure and reverse with treatment with our pacemaker. This will be achieved with state-of-the-art super-resolution microscopy and mass-spectrometry to provide both a visual and molecular analysis.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $9,480. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Tinnitus, often referred to as 'ringing in the ears', is a prevalent and disabling disorder worldwide. In New Zealand, tinnitus affects approximately 6% of the total population and severely impairs quality of life in a significant proportion of individuals. Current available treatments for tinnitus have a small effect, warranting new targeted treatment approaches. Several studies demonstrate altered activity in brain regions that are involved in the hearing processes, in individuals with tinnitus. The combined treatment of MDMA (Ecstasy) and sound therapy can normalize altered brain activity through learning, thereby reduce tinnitus perception and related distress. The current study will explore the safety and the effect of combined MDMA (Ecstasy) and sound therapy on tinnitus perception and related distress, and also evaluate its effects on the brain’s activity in the regions associated with tinnitus.

Funded by: Jean Cathie Fund for Tinnitus Research

Chronic tinnitus is a debilitating condition affecting approximately 10% of the population and for which there are limited treatment options. It has long been known that the perception of auditory signals can be modulated by a neural network called the auditory gating system, which acts as a filter to inhibit repeated irrelevant sounds. Based on this, the perception of tinnitus has been suggested to be a result of failure in this inhibitory auditory gating system. However, it is not clear what molecular changes are driving this. This project will test the involvement of the endocannbinoid system in tinnitus perception through its possible modulatory effects on auditory gating, in an animal model. Specifically, we will induce tinnitus in rats using acoustic trauma and confirm the animal’s perception of tinnitus using a well-established behavioural paradigm. We will then assess the auditory gating function using electrophysiology and measure the expression of cannabinoid CB1 receptors using radioligand autoradiography, as well as the activity of two enzymes responsible for endocannabinoid degradation, using enzyme activity assays. The results will contribute to a better understanding of tinnitus perception and lay the foundation for further studies into developing effective treatments for tinnitus, targeting the auditory gating system.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $15,309.

Funded by: Jean Cathie Fund for Tinnitus Research

Gene therapy has begun to deliver impressive therapeutic benefits for a range of human diseases, including those affecting the brain. Current strategies use a molecular Trojan horse to deposit a therapeutic gene into sick as well as healthy neurons in the target brain region. Ideally, the therapy should be restricted to sick neurons only, to reduce the potential risk of adverse effects or toxicity. We have developed a novel gene switch for use in gene therapy that harnesses disease-specific calpain signals to restrict the production of the therapy in sick cells only at the time of need. In this project, we ask whether these same disease-specific calpain signals that kickstart mechanisms that ultimately kill neurons in Huntington's disease be used to activate our gene switch and produce a therapy to halt the inevitable destruction of these same brain cells. As part of the gene-drug development process, we will confirm our gene switch works in a mouse model of Huntington's disease before we conduct a head-to-head comparison between a conventional versus our gene switch-regulated gene therapy approach. The outcomes of this work contribute a new technology that will facilitate the broad translation of gene therapy from the bench to the clinic.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $11,334. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Co-funded by the Neurological Foundation of New Zealand

This project examines the role of health systems in perpetuating inequities. Bowel cancer is a major cause of cancer death in Aotearoa, accounting for approximately 1200 deaths each year. Māori are less likely to receive care, are more likely to receive lower quality of care, and are more likely to be diagnosed with bowel cancer at an advanced stage. Each of these factors contributes to reduced survival rates for Māori compared to non-Māori. This evidence of inequity in bowel cancer treatment highlights the need to scrutinise all pathways into health services for Maori with an equity lens to determine if structural barriers at Counties Manukau DHB are contributing to the greater burden of harm from bowel cancer experienced by Maori. Internal audit data from the DHB suggest ethnic disparities exist within the referral system to endoscopy services - a key step in the process to diagnose bowel cancer. It appears that Māori do not successfully access endoscopy services at the same rates that non-Māori do. This project aims to examine the ethnic disparities, understand the barriers and enablers to access, and suggest a more equity-focused system for endoscopy services.

Funded by: Sir Lewis Ross Fund

Cancers co-opt numerous strategies to escape elimination by the patient’s immune system. Many cancers produce an enzyme called IDO1 that paralyses the cancer-killing immune cells of the patient by producing toxic chemicals. To restore the function of the cancer-killing immune cells, researchers have been developing drugs to disable IDO1. Unfortunately, one of these drugs recently produced negative results in a large clinical study. This negative outcome likely occurred because the drug could not inhibit the IDO1’s evil twin called TDO2 that cancers co-opt for the same malignant purpose as IDO1. This research aims to identify a molecule capable of inactivating both IDO1 and TDO2 at the same time. In collaboration with Australian and Swiss researchers, we will use cutting-edge robotic and computational technologies to discover molecules that disable both IDO1 and TDO2 simultaneously in cancer cells. In subsequent projects, we intend to modify the most promising molecule identified so that it permanently glues itself to IDO1 and TDO2. We reason that this “sticky” molecule will disable IDO1 and TDO2 more efficiently and will enhance the ability of patient’s immune cells to fight cancer.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $7,376. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Funded by Anonymous Donor

Immunotherapies that harness the power of the body's own immune system to kill cancer cells are revolutionising cancer therapy. However, most cancer patients are unlikely to benefit from current immune checkpoint inhibitors because the microenvironment within solid tumours impairs the activity of tumour killing immune cells (T cells). Interferon (IFN) signalling in tumour myeloid cells, another group of immune cells, activates the T cells and stimulates them to attack the tumour. However, the IFN response is diminished in tumour-infiltrated myeloid cells when they become oxygen-starved (hypoxic). The ensuing suppression of IFN responses impairs immune surveillance and renders immune checkpoint therapy ineffective. Atovaquone, a commonly prescribed anti-parasitic drug that decreases oxygen consumption rate, can abolish the hypoxic compartment in tumours. In this project, we will determine whether atovaquone can reoxygenate breast and head and neck tumour models. We will then use these models to investigate whether the loss of hypoxia decreases tumour recruitment of myeloid cells (specifically macrophages) and their co-optation into immunosuppressive states. This work will explore an important opportunity to advance immunotherapy use in the treatment of metastatic breast and head and neck cancer patients.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $9,266. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Funded by Anonymous Donor

Why do women live longer than men? 95 % of supercentenarians (110+ years old) are female, and unusually healthy. At the point of health decline, the resident organ stem cell function can no longer return the organ to homeostasis thereby linking sex and stem cells to the ageing process. We aim to elucidate the mechanisms that protect female stem cells from the ravages of ageing which leads to the prolonged health span. To date, two small animal studies have identified a disparity in the regenerative potential of stem cells from muscle tissue and in hematopoietic stem cells in mice. Simultaneously, in our studies using adult stem cells derived from human eyes, we have identified the first discernible difference between stem cells isolated from female and male human donors with the male derived stem cells showing alarmingly decreasing potency with age compared to the female cells. We propose that the eye is an ideal model in which to study the declining potency of male stem cells and enable us to determine the stem cell mechanisms as to why women live longer than men.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $8,563. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

We aim to develop a genome-engineered, regenerative skin product for people with a fragile skin condition called epidermolysis bullosa (EB). EB is caused by a defect in one of the genes that create the ‘adhesive’ that glues skin cells (keratinocytes and fibroblasts) together. Although the numbers affected are not large (approximately 150 in NZ), health care costs are considerable. The impact on the individual and families is significant due to chronic wounds, pain and complications including early mortality. Currently there is no cure for this condition. Building on our expertise of editing keratinocytes, we now want to focus our attention on editing fibroblasts. Using a small sample of patient skin, we will repair the defective gene using CRISPR/Cas9 genome engineering. "Fixing" both of the skin cell types allows us to then generate full-thickness skin sheets that could be used to permanently cover/treat the chronic wounds of EB patients. This low risk, proof of principle application combines the expertise of local, national and international clinicians, molecular and cellular biologists. In this project we are using gene editing to target a skin condition, but gene editing therapy can target a range of conditions. Therefore, this research paves the way for clinical grade gene editing in NZ and will help to build a capability with numerous clinical and research uses.

Iron plays a significant role in various biological process such as transport of oxygen around the body. In normal physiological conditions, iron in blood, is present in a bound form to the protein transferrin and is nontoxic. However, in certain pathological conditions excess free iron is found in blood, unbound to protein transferrin. This form of iron is known as non-transferrin bound iron (NTBI). NTBI is very toxic, capable of generating highly reactive free radical species responsible for oxidative damage to various organs of the body. NTBI is a potential diagnostic indicator to assess the iron status of patients at-risk. To date there is no direct method available to measure NTBI levels and excess iron is diagnosed indirectly by determining haematological clinical tests, which often underestimate free toxic iron levels and are inaccurate. Therefore, there is an urgent need for a standardised universally accepted assay method, suitable for translation into pathology laboratories. This project aims to develop an electrochemical method for accurate and rapid detection of NTBI in human blood plasma. Electrochemical techniques are advantageous due to their low cost, high speed, simplicity and has the potential to be converted into a compact biosensing kit.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $11,973. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Catheter associated urinary tract infections (CAUTIs) are one of the most common healthcare associated infections in New Zealand. Unfortunately, all catheters eventually get colonised by bacteriuria. The colonising bacteria produce “crystalline” biofilms that are highly resistant to antibiotics and block the urine flow through the catheter. This necessitates frequent removal and re-insertion of the catheter causing significant discomfort and emotional burden on patients. Current mitigation strategies to prevent bacterial accumulation onto urinary catheters include developing antifouling and antimicrobial surfaces. Unfortunately, these modified catheters have several drawbacks such as lack of long-term efficacy due to bacterial accumulation, development of bacterial resistance and cytotoxicity. From our previous research, we have identified a series of novel peptide-based therapeutics with broad spectrum antibacterial and antibiofilm activity against several uropathogens Escherichia coli, Pseudomonas aeruginosa and Candida albicans. Silicon surfaces immobilized with the most potent peptide, were not colonized by biofilms. This proposal tackles one of the long-term efficacy issues associated with urinary catheters that arises from the accumulation of dead bacteria on catheter surfaces. A novel pH responsive antibiofilm self-cleaning urinary catheter coating will be developed combining the antimicrobial power of our peptide therapeutics with the pH responsiveness of natural dextran polymers.

Kidney disease is a major health concern in New Zealand (NZ) with 11% of the population thought to have some form of chronic kidney disease (CKD). Podocytes are specialised cells that form the kidney's blood filters, and they are the major target of injury in CKD. Currently, therapies do not target podocytes but instead act systemically and often with limiting side-effects. We have identified a NZ family with a unique inherited kidney disease that is associated with a mutation in the WT1 gene, a key regulator of podocyte function. The goal of this proposal is to use state-of-the-art human kidney organoids (mini kidneys grown in a dish) to establish a model of the patients’ kidney defects. This will help us understand how the WT1 mutation leads to disease. In addition, we will use these organoids to test the therapeutic effects of a drug-like compound that we found can ameliorate the effects of the WT1 mutation, thereby helping advance the development of a new therapy for CKD in the future.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $11,330. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Small size at birth caused by fetal growth restriction (FGR) decreases a baby’s chances of survival and can have negative consequences for health throughout life. Using current methods, measuring the size of the mother’s tummy or ultrasound, miss at least a third of cases in New Zealand and more worldwide. These missed cases are at increased risk of stillbirth. FGR is usually accompanied by low blood oxygen content in utero because the placenta is not working properly. Measuring fetal blood oxygen content is not possible in human babies but we can do so in sheep fetuses. A hormone called C-type natriuretic peptide (CNP), found in maternal blood, may be a marker of low fetal blood oxygen and FGR. This study will investigate whether CNP could be a useful test for FGR, detecting it more reliably and with an inexpensive, noninvasive test that does not require specialist skills. We will study the detailed relationship between fetal blood oxygen and maternal CNP in sheep to inform future research in women and their babies.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $3,167. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Co-Funded by Cure Kids

The impact of Covid-19 restrictions has been profound for people who have experienced the death of a whānau or family member since we first moved to Level 4 in March 2020. During Lockdown many people died alone due to visitor restrictions, with family/whānau grief exacerbated by an inability to hold tangihanga and funerals and even under Level 1 measures arranging visits from overseas relatives is complex. Understanding the circumstances – and experiences – of end of life care and dying from the family/whānau perspective is critical to informing national guidelines regarding optimizing palliative and end of life care during pandemics. Working in partnership with Auckland and Counties DHBs, we will conduct a mixed methods study involving over 1,000 bereaved family and whānau caregivers and approximately 60 health professionals, NGO and community development workers. Findings will inform the development of evidence-based guidelines and an inter-professional education resource to support DHBs, Hospices, Primary Healthcare Organisations, Aged Residential Care Facilities and the Ministry of Health in planning how to ensure high quality and equitable palliative and end of life care during pandemics.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $7,889. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Many anticancer drugs cause heartburn and patients are often given proton pump inhibitor (PPI) drugs to help with these symptoms. Capecitabine is a tablet form of 5-Fluorouracil, which is given intravenously. Capecitabine is converted in the body by a multi-step process prior to formation of 5-Fluorouracil. Recent studies suggest that individuals prescribed PPI drugs with capecitabine have poorer disease survival than patients treated with 5-Fluorouracil and PPI drugs. The reason for this difference is not known. One suggestion is that changes in the pH of the stomach from use of PPI affects the dissolution of the tablet and decreases how much capecitabine enters the body. However, the only published information on the effect of PPI on capecitabine blood concentrations was a flawed study. Hence it is not known if there is this type of interaction between PPI and capecitabine. We will undertake a series of studies to assess whether PPI adversely affect the absorption of capecitabine tablets in patients and to also investigate other mechanisms of how PPI may interfere with capecitabine action in cells grown in the laboratory. By understanding how PPI drugs interact with capecitabine we can help NZ oncologists decide whether it is appropriate to prescribe these drugs together.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $3,267. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Co-Funded by Cancer Research Trust New Zealand

The immune system has evolved to anticipate and prepare for daily fluctuations in bacterial exposure by coordinating a heightened antibacterial response. This cunning adaptation is believed to be regulated by a molecular timer (or clock) that operates in immune cells and tissues to elevate antibacterial responses when we are active, and exposure to pathogens is greatest. Given genetic or environmental disruption of this molecular timer (e.g. from shift work or jet lag) enhances the risk of infection, pharmacologic targeting of the molecular clock, and specific timing of antimicrobial therapies, are emerging as exciting new approaches to treat infections. To realise this therapeutic potential, we need to understand how these molecular timers operate within different components of the immune system to fight infections. We have evidence that a molecular clock regulates the activity of a powerful weapon of the immune system that detects and eliminates bacterial infections, called the complement system. This project will uncover exactly how the molecular clock regulates oscillations in complement antibacterial activity and whether targeting the molecular clock can elevate this antibacterial response. We expect this knowledge will unlock new approaches to fight infections around the clock.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $7,938. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

In New Zealand we can assess people’s future risk of cardiovascular disease (CVD), heart attacks and related diseases, to help decisions particularly about lipid-lowering and blood pressure lowering treatments. About 500,000 patients are in this GP-based system, called PREDICT. Cancer is a long-term disease. In NZ, 64% of cancer patients are alive more than five years after diagnosis, with about 15,000 in PREDICT. There are about 95,000 cancer survivors in NZ. Apart from cancer, the greatest risk to these patients is CVD. We will test whether PREDICT gives accurate results for those with cancer, and test if it can be improved for cancer patients. We will assess whether the risks of CVD are increased in cancer patients. We will give particular attention to Māori and Pacific populations, who have higher rates of CVD and higher rates of death from cancer. We will also use another less detailed system, VARIANZ, with over 70,000 cancer patients. This study uses non-identified data from several sources, with strict confidentiality and data protection systems. No individual patients need to be approached. This research will give valuable new information on CVD and cancer, and improve the treatment of individual patients, and health policies and systems.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $8,091. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Funding contribution: Rose Richardson Estate

Cystic fibrosis (CF) is the most common life-shortening inherited disease in New Zealand. There is currently no cure for this disease and life-long treatment is required. Patients with CF produce thick mucus that they then have difficulty clearing from their airways. As a result, CF patients suffer from repeated bacterial infections and are prescribed several courses of antibiotics, which increase the risk of developing antibiotic resistance. Although the bacterial pathogens found in the lungs of CF patients have been researched extensively, it remains unclear if the same pathogens are also found in the sinuses. Our project proposes a long-term study that investigates the bacteria in the sinuses and lower airways within the same CF patient throughout acute infections and when patients are clinically stable. Specifically, we will apply sequencing techniques to evaluate the transmission of bacteria between airway sites within the same patient and assess changes in antibiotic resistance over time. This will be the first study in NZ to examine longitudinally the sinus and lung microbiomes of adult patients with CF. This project will contribute significantly new knowledge about the dynamics of the bacteria in the CF airway and help improve antibiotic treatments for this lifelong condition.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $7,152. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

There is currently little knowledge about self-harm, and a lack of resources to support whānau (families) that have been developed and tested in New Zealand. This lack of whānau knowledge can increase the level of distress and isolation that young people feel and may lead to worsening mental health of both the whānau and the young person. This research uses a specific bicultural approach of He Awa Whiria (the braided rivers approach) which ensures that a kaupapa Māori approach is able to sit alongside but be separate from the Pākehā approach, although they may also influence each other. By using this approach, the research will create a resource, which is both by and for Māori to support Māori whānau using their own experiences, and those of their young people. The development of co-designed resources based on current best practice and will improve access to tools that can help whānau support their young person and enhance the wellbeing of the young person and the whānau alike. This improved wellbeing may reduce the severity and frequency of self-harm and potentially reduce hospital admissions for self-harm requiring medical attention.

The development of head-mounted miniaturised microscopes (miniscopes) enables brain activity to be recorded in freely moving rodents. By using miniscopes we can directly decipher how brain cell activity underlies behaviour as it happens in the awake behaving animal. Furthermore, we can utilise this technology to understand the mechanisms of behavioural changes in neurological diseases. Here we will examine the cellular mechanisms that underlie behavioural deficits in Autism Spectrum Disorders (ASD). Individuals with ASD display a range of behavioural changes including learning difficulties, social deficits, and repetitive behaviours. These behaviours are well replicated in mouse models allowing their cellular underpinnings to be explored. Several of the behaviours that are affected in ASD are mediated by a brain region called the hippocampus. We will utilise miniscopes to examine cellular activity in the hippocampus during spatial and social memory tasks. We will also determine whether a dietary zinc supplement, previously shown to prevent ASD behaviours from developing, returns hippocampal activity to normal. The ability to examine brain activity and behaviour simultaneously will advance our understanding of the cellular mechanisms that cause behavioural deficits in ASD. Improved understanding of the mechanism of action of our treatment will aid its translation into clinical trials.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $7,029. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Immunotherapies like Keytruda offer people diagnosed with Malignant Melanoma an effective new choice for treatment. Identifying if a cancer is responding to these therapies is however challenging, limited to physical exam and imaging. Testing of the blood could detect people who do not respond much earlier thereby reducing the side effects and saving inconvenient travel to receive these treatments. International scientists have identified a new early detection marker of treatment response that analyses vesicle packages from the blood. Now the challenge remains to bridge the gap between research and hospital laboratories. For this purpose, our study will develop a state of the art microfluidic technology to provide a rapid, inexpensive and sensitive testing method for trial using patient blood samples. This study aims to firstly confirm in Aotearoa NZ patients that these vesicles can accurately detect whether an individual is responding to treatment. Secondly, we aim to build new expertise and offer training in bio-engineering to upskill new researchers. Finally, and most importantly, we will take steps towards the development of a clinically useful test that ultimately could improve patient outcomes and reduce inequities in testing through the provision of a portable, quick and inexpensive technology.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $8,400. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Funded by JI Sutherland Fund for Melanoma Research

The lymphatic vasculature plays an essential role in fluid homeostasis where it collects excess tissue fluid and returns it to the bloodstream. Lymphatic vessels also provide a conduit for immune cell trafficking and therefore help to regulate our immune response. Dysregulated lymphatic vessel growth underpins many health conditions, ranging from cancer metastasis, kidney transplant rejection and breast cancer-associated secondary lymphoedema. In New Zealand, over 20% of women who undergo lymph node removal and/or radiotherapy as part of treatment for breast cancer will develop lymphatic dysfunction and secondary lymphoedema - the painful and debilitating buildup of fluid in tissues. In contrast, the aberrant overgrowth of lymphatic vessels is associated with cancer metastasis and can also cause the mis-trafficking of inflammatory cells, contributing towards the rejection of transplants. Consequently, there is considerable interest in therapies that can regulate lymphatic vessel growth to help treat these lymphatic-related conditions. However, the mechanisms that control lymphatic growth remain understudied. In this project we will address this by analysing zebrafish mutants that display either excessive lymphatic growth or a lack of lymphatic vessels, allowing us to determine how lymphatic vessel growth is controlled during development. This important work will pave the way for new therapies to treat lymphatic-related disease.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $6,793. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

In the last 20 years it has become very common for pregnant women in New Zealand to develop diabetes; 10% of women who didn’t have diabetes before becoming pregnant will have diabetes in pregnancy. Diabetes in pregnancy increases the risk of complications during pregnancy and when the baby is born. A healthy diet and exercise and, in some cases, medicine such as insulin, reduces the risk for women with diabetes in pregnancy. However, it is unknown if there are long-term risks for the baby’s brain development and risk of obesity if they are born to a mother who had diabetes in pregnancy. In this study we will compare children who were born to mothers with diabetes, with those whose mothers didn’t have diabetes, at 6-7 years of age. We will assess the children’s ability to do well at school and their body composition. The results of this study will give valuable information on the long-term outcomes of children who are born to mothers who develop diabetes in pregnancy.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $5,017. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Cisplatin chemotherapy is considered a mainstay of cancer treatment. However, the growing population of cancer survivors demands better management of long-term side effects of cisplatin treatment. Following cisplatin chemotherapy, 40-80% of adult patients and at least 50% of paediatric patients are left with permanent hearing loss. Currently, there are no treatments available to mitigate or reverse cisplatin-induced hearing loss, other than dose reduction or switching to non-cisplatin treatments. Both alternatives may have negative impacts on cancer treatment outcomes, hence hearing loss risk must be carefully weighed against therapeutic efficacy. This preclinical study is focused on damaging effects of cochlear inflammation as a result of systemic cisplatin administration. We aim to investigate the molecular mechanisms that contribute to resolution of cochlear inflammation and then develop a novel strategy for preventing hearing loss associated with cisplatin chemotherapy. Proposed studies are directly relevant for the prevention of hearing loss in cancer patients treated with cisplatin and other platinum-based chemotherapeutic agents.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $15,482. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Hearing loss is a global problem; according to the 2017’s report from the National Foundation of Deaf, in New Zealand, 880,000 people are estimated to be living with some degree of hearing loss in 2016. Hearing aids and cochlear implant technologies can provide improvement, albeit at significant cost to our economy, and these technologies cannot reverse the underlying pathology. There is a strong need for new therapeutic interventions to prevent the progression of underlying pathology and to facilitate recovery of the residual hearing. Our sense of hearing starts in the inner ear organ called cochlea, where “hair cells” respond to incoming sound and this information is propagated to our brain by auditory neurons. Recent research suggested the loss of communication between hair cells and neurons to be the major underlying cause of hearing loss. We have hypothesis that a group of ATP-receptor proteins are important for maintaining the connections between hair cells and neurons. In this proposal, we will test this hypothesis, in hope to identify these proteins as novel therapeutic targets that can prevent the loss of synaptic connections in the cochlea, and even reverse it by facilitating re-connection between hair cells and auditory neurons. Co-funded by: Eisdell Moore Centre

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $13,432. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Antibody drug conjugates (ADC) are an exciting development in treating breast cancer. These elegant engineered molecules can be envisioned as “heat-seeking missiles” that seek out cancer cells using a precision antibody and then deploy a “payload”, a toxic molecule that will destroy the cancer cell. This approach towards targeted cancer therapy is exemplified by trastuzumab emtansine (tradename Kadcyla™) that can effectively treat drug resistant breast cancers. There are over 60 ADCs in development, but each of them deploys only one of two different types of cancer-killing payloads – this lack of diversity is a serious impediment to progress. To address this problem, studies led by Dame Professor Margaret Brimble have discovered a novel cancer-killing payload called AN-58. AN-58 appears to kill cancer cells by disrupting membranes – the biological barriers that enclose and separate parts of cells. It is critical that we fully understand this cancer killing mechanism. We believe that AN-58 kills cancer cells by “punching” holes in their membranes – but seeing is believing. We will make artificial membranes that mimic cells and then use super-powerful electron microscopes to directly visualise how AN-58 destroys cancer cells!

New Zealand’s largest and fastest growing health problem is type 2 diabetes (T2D). Elevated blood sugar levels associated with T2D increases the risk of developing many related diseases like cardiovascular disease (CVD), liver disease, stroke and microvascular complications that lead to blindness, amputations and chronic kidney failure. Genetics is a major factor contributing to an individual’s risk of developing T2D. Recently a small change in a gene called CREBRF has been shown to be protective against the development of T2D. This genetic variation is present in 20-30% of people of Polynesian ancestry living in New Zealand. We currently do not know how this variant protects from T2D, but we do know that the pancreas produces a hormone called insulin, and insulin is responsible for lower blood sugar levels after a meal. When T2D develops the pancreas’s ability to produce insulin is reduced, causing a rise in blood sugar levels. In this project we will investigate whether the genetic variant in the CREBRF gene may be protecting the pancreas cells from damage, and this leads to a reduce T2D risk in some people of Māori and Pacific ancestry.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $16,732.

The microenvironment in which tumours grow is low in oxygen, acidic and deficient in nutrients. Tumours must adapt to these stressful conditions to survive and do so through changes in gene regulation. However, many of the genes responsible for promoting survival of tumour cells within this hostile microenvironment remain unknown. Using a method called a functional genomics screen, we have systematically identified genes in head and neck cancer cells that could modulate tolerance to various microenvironment stressors, including low oxygen, acidic pH and nutrient deprivation. In this project, we plan to validate the findings of our functional genomics screens by individually investigating these identified genes. In doing so, we will improve our understanding of the biology that underpins tumour cell survival in these hostile conditions, as well as uncover potential new targets for therapeutic intervention in head and neck cancer.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $13,432. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

This work focuses on patients with essential thrombocythaemia (ET) and primary myelofibrosis (PMF). Both are chronic but incurable blood cancers characterised by abnormal platelet counts in the blood and atypical platelet precursors in the bone marrow. While patients with ET have a near-normal life expectancy, survival of patients with PMF is significantly shorter. The reason for the difference is unclear, as both ET and PMF share the same driver mutations. We hypothesise that an adaptive pro-survival response in bone marrow cells determines the disease phenotype. Simply, driver mutations are damaging and cause cell “stress”. Cancer cells find ways to counteract the stress by recruiting certain pro-survival mechanisms, which allows driver mutations to cause the disease. As the pro-survival response strengthens, the disease becomes more damaging. We will use bone marrow samples from patients to identify pro-survival mechanisms recruited in ET and PMF. Findings will be correlated with patient diagnosis and driver mutations. Then, small molecules will be chosen to inhibit cell stress response in culture, with an idea that selected molecules may help restrict mutational effects. Our results will provide proof-of-concept evidence that drugs that inhibit cell stress response can help control disease manifestations in patients.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $17,932. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

The number of people afflicted by cataracts is estimated to reach 30 million as the world’s population ages. Faced with a looming cataract epidemic, research has focused on developing anti-cataract therapies to prevent cataract and reduce the need for surgery. Since cataract is associated with decreased levels of antioxidants specifically in the lens centre, the use of dietary antioxidant supplements has been advocated as a therapeutic approach to slow cataract progression. However, studies into their efficacy are mixed due to an inability to target their delivery. Our research first addresses a fundamental question on how lens physiology and metabolism maintains tissue transparency, and lays the foundation to then pharmacologically harness lens physiology to deliver therapeutic molecules to specific regions of the aging lens to delay or prevent the onset of lens cataract. First we will assess our ability to pharmacologically stimulate the lens to deliver nutrients to the nucleus, before then packaging therapeutic molecules in nanovesicles to enable their delivery to the lens nucleus. This will determine whether we can enhance the lens antioxidant defence system and prevent or delay the onset of cataract, for which no preventative treatment currently exists.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $18,884. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

The proteins in the center of your eye lens have been with you since you were born. Although these proteins are tough, they breakdown and change over their long lifetime. This change is necessary for normal eye function; however, it can also result in negative effects. On such outcome is presbyopia, which is the loss of near vision due to a stiffening of the lens. It is thought to be caused by accumulation of large, inflexible protein assemblies. In most, these collections of proteins are non-hazardous; however, under certain conditions they can cause the eye to become cloudy and form the disease cataract. How these proteins change their structure with age and position in the lens for positive and negative health outcomes is still unknown. Like a topographical map, this work will map the identity and structure of proteins directly from the lens to understand how they change with age and disease state. These results can be used to develop early detection schemes, and to help design the next generation of therapies to alleviate these diseases.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $12,338. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

Stroke is the third most common cause of death in New Zealand and is one of the leading causes of long-term disability at all ages. A life-saving clot retrieval procedure can save the lives of patients who get to hospital within the first six hours of having an ischaemic stroke (caused by a blood clot). The clot can be removed using a mesh like retrieval device, freeing the clot from the brain. Getting a patient to hospital quickly following symptoms of a stroke can be life-saving with longer delays indicating poorer outcomes. In New Zealand, 90% of clot retrieval procedures are performed under general anaesthesia. Under anaesthesia during stroke, blood pressure (BP) management is critical. Many anaesthetic drugs can affect the blood flow within the brain. There is a possible mechanism of benefit from an increased BP target. A large randomized control trial is the only way to reliably investigate BP management during clot retrieval and further improve outcomes from stroke.

Preeclampsia is a disease found only in pregnant women. A woman with a preeclamptic pregnancy has dangerously high blood pressure which results in damage to many of her organs and can potentially cause her death. The only way to prevent this, is to deliver the baby, often prematurely with long-term consequences for the baby. Mothers who have preeclamptic pregnancies also have long-term risk of heart disease and stroke. We do not know exactly what causes preeclampsia but we do know that toxins released from the placenta cause damage to mum’s blood vessels resulting in high blood pressure/preeclampsia. The nature of the placental toxins is not known, but we have shown that extracellular vesicles, tiny packages from the placenta, are different between preeclamptic and normal placentas and that preeclamptic vesicles are toxic to maternal blood vessels. Extracellular vesicles carry a large number of proteins that could be toxic but only a few of these have been identified. In this project we will use a newly developed technique to characterize all of the proteins in preeclamptic extracellular vesicles to see which are toxic. We will also give preeclamptic vesicles to pregnant mice to confirm that these vesicles cause high blood pressure/preeclampsia.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $16,908. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

In this study we will use our combined expertise in clinical cardiology, cardiac electrophysiology and neurophysiology to perform novel research into the interactions between sympathetic neurons and heart cells in inherited arrhythmia syndromes. Specifically, we will focus on Long QT Syndrome (LQTS), the most common cause of sudden death in New Zealand youth. LQTS arrhythmias are typically triggered by the sympathetic “fight-or-flight” response. Treatment strategies including beta-blockers and sympathectomy (the surgical cutting of a sympathetic nerve to break the neuron-heart cell connection), although the underlying mechanisms remain poorly understood. Also, exactly how these sympathetic neurons cause cardiac arrhythmia in LQTS is unknown. Recent breakthroughs make it possible to model neuro-cardiac interactions in vitro. Using induced pluripotent stem cells (iPS cells) that we have reprogrammed from LQTS patient and control blood, we will grow sympathetic neurons and heart cells together. These co-cultures will enable us to directly study the neuronal regulation of heart rate and action potential duration using cellular electrophysiology techniques, and find out what differs in the LQTS patient-derived cells that causes the arrhythmia. A better understanding of the underlying neurocardiac arrhythmia mechanisms could enable improved risk management, tailored therapies and new treatment targets for LQTS families.

After a hip or knee joint replacement it is important to mobilise (get out of bed and move) early to recover faster, and reduce the risk of complications after surgery. Mobilisation can be hindered by orthostatic intolerance, described as the development of symptoms (dizziness, nausea, vomiting, blurred vision, feeling of heat, and fainting) when standing upright. Orthostatic intolerance has been reported to happen in up to 60% of patients after surgery. Reasons include an inability of the peripheral blood vessels to constrict (tighten) properly in response to standing. Midodrine is a drug working by constricting the peripheral blood vessels, thereby improving blood pressure. This study aims to investigate if midodrine can reduce the occurrence of orthostatic intolerance after hip and knee joint replacements. One-hundred and seventy patients will be randomised to receive either midodrine or placebo in the early postoperative period. OI will be assessed on the day of surgery, and on the first day after surgery. Midodrine is effective in treating chronic orthostatic intolerance and we believe the administration will reduce the occurrence of orthostatic intolerance in patients after hip and knee joint replacements. This may lead to faster recovery and shorter stay in hospital.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $27,720.

Our ability to form memories and learn is fundamental to the way we experience life. These processes are coordinated by highly-specific and wire-like connections from neuron cells in the hippocampal region of the brain, which mostly develop before birth and during early childhood. However, these become disrupted in infants diagnosed with brain injury after low oxygen and glucose availability during birth. Survivors show abnormal neuron growth and activity (typified by seizures and learning problems), affecting brain functions throughout later life. However, scientists and clinicians are still challenged by why and how low oxygen and glucose affects neuronal development. We recently found that young neurons produce a key sugar called ‘hyaluronan’, which normally controls their growth. However, experimentally restricting brain blood flow, and thereby limiting oxygen and glucose supply, caused a loss of brain hyaluronan. We now propose that a loss of hyaluronan causes the abnormal neuronal development in young infants. The main objective of this study is to explore how abnormal levels of hyaluronan may alter hippocampal neuron development following a reduction in the supply of oxygen and glucose to the brain. The ultimate goal is to explore whether hyaluronan can restore brain development in affected infants.

In March 2022, the AMRF Covid-19 Relief Fund provided an additional $15,484. This was matched by a similar contribution from the University of Auckland’s Covid Hardship Fund.

One in three New Zealanders have high blood pressure, which can cause stroke, kidney and heart failure. Its asymptomatic characteristic means it can go undetected. More alarming is that half of those patients on medication do not have their blood pressure controlled suggesting that current medications are not effective. The proposed project will establish if the reason blood pressure goes up relates to changes in the detectors of carbon dioxide (CO2), a product of metabolism, in blood. These detectors are located in the carotid arteries and the brainstem and powerfully increase blood pressure when stimulated. Patients will be recruited from a recently formed high blood pressure network spanning five district health boards. In a brand new specialist Human Research Laboratory within the ADHB, we will determine whether CO2 detectors are sensitised in people with high blood pressure. We believe they are and that the detectors in the carotid artery are, in part, responsible for the sensitivity of brainstem CO2 detectors. Our findings may reveal a novel mechanism for why people become hypertensive. This information will be critical for developing new management strategies to control blood pressure using both repurposed drugs and medical devices, which may become available to us in due course.