Project Grants

2022
6 awards

$1,013,442 to date

2021
18 awards

$2,407,864

2020
22 awards

$2,840,065

2019
19 awards

$2,489,420

In March 2022 an additional $625,000 was awarded to 55 researchers from the Covid-19 Relief Fund in order that their research could continue despite the significant delays and disruptions caused by Covid-19 lockdowns.

DOPAMINE AND TINNITUS ($69,680 – 1 year) 7722005

2022

Dr Yiwen Zheng, Professor John Reynolds, Professor Paul Smith

Dept. of Pharmacology and Toxicology, The University of Otago

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

PROTECTING THE GUT FROM ISCHAEMIC INJURY ($175,353 – 2 years) 1122006

2022

Dr Sachin Thakur, Dr Anthony Hickey, Prof Anthony Phillips, ProfJohn Windsor

School of Pharmacy, The University of Auckland

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.

COMPASS FEASIBILITY STUDY ($179,980 – 2 years) 1122003

2022

Dr Anna Serlachius, Prof Nathan Consedine, Dr Sarah Hopkins, Dr Alana Cavadino, Ms Anna Boggiss, Ms Susan Reid, Mr Nicholas Cao, A/Prof Craig Jefferies, Dr Martin de Bock,

Dept. of Psychological Medicine, The University of Auckland

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.

GONOCOCCUS VACCINES ($145,632 – 2 years) 1122004

2022

Prof Thomas Proft, Dr Catherine (Jia-Yun) Tsai, Dr Fiona Radcliff, Dr Joanna Hicks

Dept. of Molecular Medicine & Pathology, The University of Auckland

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.

NOVEL TREATMENT FOR DIABETIC HEART DISEASE ($172,920 – 2 years) 1122001

2022

Dr Kimberley Mellor, Mr Marco Annandale, Prof Lea Delbridge

Dept. of Physiology, The University of Auckland

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.

BIOMARKERS FOR FOETAL COMPROMISE ($160,051 – 2 years) 1122002

2022

Dr Christopher Lear, Prof Laura Bennet, Prof Alistair Gunn, Dr Simerdeep Dhillon

Dept. of Physiology, The University of Auckland

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.

PAEDIATRIC PALLIATIVE CARE EDUCATION AOTEAROA ($109,826 – 2 years) 1122005

2022

Dr Gemma Aburn, Dr Ross Drake, Dr Deborah Raphael, Dr Tess Moeke-Maxwell

School of Nursing, The University of Auckland

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.

ANTIBIOTIC HYBRIDS AGAINST AMR ($159,991 – 2 years) 1121018

2021

Dr Andrew Thompson, Professor Greg Cook, Dr Veronica Playle

Auckland Cancer Society Research Centre, The University of Auckland

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.

USING IN-SITU SIMULATION TO RESOLVE THREATS TO PATIENT SAFETY ($46,000 – 2 years) 1121017

2021

Professor Jennifer Weller, Dr Carlos Campos, Dr Jennifer Long, Ms Kaylene Henderson, Dr Andrew MacCormick, Professor Alan Merry

Centre for Medical and Health Sciences Education, The University of Auckland

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.

CONNEXIN 43 AND PRETERM BRAIN INJURY ($159,351 – 2 years) 1121016

2021

Dr Justin Dean, Dr Joanne Davidson, Professor Alistair Gunn, Dr Panzao Yang

Dept. of Physiology, The University of Auckland

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.

PHARMACOKINETICS OF PERIOPERATIVE LIGNOCAINE ($64,810 - 2 years) 1121015

2021

Dr Jacqueline Hannam, Dr Daniel Chiang, Associate Professor Malcolm Tingle

Dept of Pharmacology & Clinical Pharmacology, The University of Auckland

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.

EXPERIENCES OF THE END OF LIFE CHOICE 2019 ACT AMONGST HEALTH PRACTITIONERS, WHĀNAU AND FAMILIES ($156,142 – 2 years) 1121014
Dr Gary Cheung, Dr Rosemary Frey, Associate Professor Frederick Sundram, Associate Professor

2021

Dr Gary Cheung, Dr Rosemary Frey, Associate Professor Frederick Sundram, Associate Professor Sarah Cullum, Associate Professor Susan Bull, Associate Professor David Menkes, Dr Nicholas Hoeh, Dr Alisha Vara, Dr Adam Sims, Dr Jackie Robinson, Dr Deborah Balmer, Dr Melissa Carey, Dr Helen Cassidy

Dept. of Psychological Medicine, The University of Auckland

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.

THE INFLAMMASOME AND DIABETIC RETINOPATHY ($155,995 – 2 years) 1121013

2021

Dr Odunayo Mugisho, Dr Rinki Murphy

Dept. of Ophthalmology, The University of Auckland

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.

FROM CRISIS TO RECOVERY: PROTECTING CHILD HEALTH AND WELL-BEING THROUGHOUT THE PANDEMIC ($159,611 – 2 years) 1121012

2021

Associate Professor Annette Henderson, Professor Nickola Overall

Dept. of Psychology, The University of Auckland

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.

VERIFICATION AND FUNCTIONAL CHARACTERISATION OF AQP3 IN THE LENS ($113,016 – 2 years) 1121011

2021

Dr Rosica Petrova, Professor Paul Donaldson, Dr Julie Lim

Dept. of Physiology, The University of Auckland

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.

ARRHYTHMOGENIC CALCIUM LEAK IN DIABETES ($158143 – 2 years) 1121010

2021

Dr Marie-Louise Ward, Dr Kenneth Tran, Dr Amelia Power, Professor Peter Ruygrok

Dept. of Physiology, The University of Auckland

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.

FAIR-ACS ($125,835 – 2 years) 1121009

2021

Dr Nikki Earle, Professor Rob Doughty, Dr Katrina Poppe, Dr Anna Rolleston, Associate Professor Malcolm Legget

School of Medicine, The University of Auckland

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.

ELIMINATING GROUP A STREPTOCOCCUS ($160,000 – 2 years) 1121008

2021

Dr Alan Cameron, Dr Jia-Yun Tsai, Professor Thomas Proft, Distinguished Professor Dame Margaret Brimble

School of Chemical Sciences, The University of Auckland

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.

VAPOR-C TRIAL ($142,668 - 2 years) 2121004

2021

Dr Anna Waylen, Professor Tim Short, Dr Doug Campbell, Dr Greg O'Grady, Dr Ben Lawrence, Dr Sarah Nicolson

Anaesthesia Department, Auckland District Health Board

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.

rEPO AND HYPOTHERMIA FOR NEONATAL ENCEPHALOPATHY ($160,000 - 2 years) 1121001

2021

Dr Guido Wassink, Professor Alistair Gunn, Professor Laura Bennet

Dept. of Physiology, The University of Auckland

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.

PACE C: INTERNATIONAL RANDOMISED STUDY OF CONVENTIONALLY FRACTIONATED RADIOTHERAPY VS SBRT FOR ORGAN-CONFINED PROSTATE CANCER ($68,320 - 1 year, 5 months) 2121005

2021

Dr Giuseppe Sasso, Dr Maria-Lee Pearse

Radiation Oncology Department, Auckland District Health Board

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.

COVID-19 VACCINATION IN PATIENTS WITH CHRONIC KIDNEY DISEASE - NEW ZEALAND (C-VAK NZ study) ($159,505 - 12 months) 2121006

2021

Associate Professor Helen Pilmore, Dr Michael Collins, Dr Ian Dittmer, Professor Germaine Wong, Dr Paul Manley, Dr Sally Roberts

Dept. of Renal Medicine, Auckland District Health Board

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.

BM12 CAST STUDY: CYCLOPHOSPHAMIDE AFTER SIBLING-DONOR ALLOGENIC STEM-CELL TRANSPLANTATION ($98,982 - 2 years) 2121002

2021

Dr Clinton Lewis, Dr Richard Doocey, Dr Timothy Hawkins, Professor Peter Browett, Dr Nicole Chien

Cancer and Blood Services, Auckland District Health Board

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.

SYNTHETIC LETHALITY AND DNA DAMAGE RESPONSE ($159,636 - 2 years) 1121007

2021

Associate Professor Michael Hay, Dr Barbara Lipert, Dr Tet-Woo Lee, Dr Stephen Jamieson

Auckland Cancer Society Research Centre, The University of Auckland

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.

NATURE'S PACEMAKER ($159,859 - 2 years) 1121003

2021

Dr David Crossman, Dr Jizhong Bai, Dr Kyriakos Varnava, Dr Angus Grey, Dr Rohit Ramachandra, Professor Julian Paton

Dept. of Physiology, The University of Auckland

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.

NOVEL TREATMENT FOR TINNITUS ($74,803 - 2 years) 7720016

2020

Professor Dirk De Ridder, Dr Yiwen Zheng, Dr Grant Searchfield, Associate Professor Bruce Russell, Dr Divya Adhia, Professor Paul Glue, Professor Paul Smith

Surgical Sciences, University of Otago

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

ENDOCANNABINOIDS AND TINNITUS PERCEPTION ($74,916 - 1 year) 7720015

2020

Dr Yiwen Zheng, Dr David Finlay, Professor Paul Smith, Professor Michelle Glass

Department of Pharmacology and Toxicology, University of Otago

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

A NOVEL GENE REGULATION SYSTEM FOR USE IN GENE THERAPY ($158,550 - 2 years) 1120003

2020

Associate Professor Deborah Young, Dr Angela Wu

Dept. of Pharmacology & Clinical Pharmacology, The University of Auckland

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

ACCESS TO ENDOSCOPY FOR MAORI AT CMDHB ($10,580 - 6 months) 3120006

2020

Ms Maree Weston, Dr Andrew MacCormick, Ms Emma Espiner, Associate Professor Elana Curtis

Department of General Surgery, Middlemore Hospital, Counties Maunkau District Health Board

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

BANISHING TRYPTOPHAN CATABOLISM ($159,056 - 2 years) 1120009

2020

Dr Petr Tomek, Associate Professor Brian Palmer, Associate Professor Kaylene Simpson, Associate Professor Ute Röhrig

Auckland Cancer Society Research Centre, The University of Auckland

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

ATOVAQUONE FOR IMPROVED CANCER IMMUNOTHERAPY ($159,275 - 2 years) 1120013

2020

Dr Dean Singleton, Dr Kimiora Henare, Dr Stephen Jamieson, Dr Tet-Woo Lee

Auckland Cancer Society Research Centre, The University of Auckland

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

AS OLD AS YOUR STEM CELLS ($159,975 - 2 years) 1120007

2020

Professor Trevor Sherwin, Dr Julie Lim

Dept. of Ophthalmology, The University of Auckland

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.

GENOME-CORRECTED FIBROBLASTS FOR USE IN 3D SKIN SHEETS ($160,000 - 2 years) 1120018

2020

Dr Hilary Sheppard, Dr Sarah Meidinger, Dr Vaughan Feisst, Dr Diana Purvis

School of Biological Sciences, The University of Auckland

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.

ELECTROCHEMICAL DETECTION OF IRON ($155,032 - 2 years) 1120016

2020

Dr Manisha Sharma, Associate Professor Darren Svirskis, Professor Paul Kilmartin, Professor Anthony Phillips, Dr Claire Hemmaway

School of Pharmacy, The University of Auckland

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.

SELF-CLEANING ANTIMICROBIAL SURFACES ($160,000 - 2 years) 1120012

2020

Dr Viji Sarojini, Professor Jadranka Travas-Sejdic, Associate Professor Jun Lu

School of Chemical Sciences, The University of Auckland

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.

ORGANOIDS, KIDNEY DISEASE AND DRUG DEVELOPMENT ($150,000 – 15 months) 1120002

2020

Dr Veronika Sander, Associate Professor Alan Davidson, Dr Janak de Zoysa, Dr Thitinee Vanichapol

Dept. of Molecular Medicine & Pathology, The University of Auckland

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.

CNP AND FETAL GROWTH RESTRICTION ($50,680 – 2 years) 1120017

2020

Dr Mark Oliver, Associate Professor Katie Groom, Professor Frank Bloomfield, Professor Eric Espiner, Dr Timothy Prickett

Liggins Institute, The University of Auckland

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

END OF LIFE CARE DURING COVID-19 RESTRICTIONS ($120,079 - 18 months) 1120010

2020

Dr Tess Moeke-Maxwell, Professor Merryn Gott, Dr Jackie Robinson, Dr Lisa Williams, Dr Rosemary Frey, Associate Professor Janine Wiles, Dr Melissa Carey, Dr Natalie Anderson, Dr Jenny Parr

School of Nursing, The University of Auckland

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.

DO PPI DRUGS ADVERSELY INTERACT WITH CAPECITABINE ($81,174 - 2 years) 1120011

2020

Associate Professor Nuala Helsby, Dr Edmond Ang, Dr Sanjeev Deva, Dr Soo Hee Jeong

Dept. of Molecular Medicine & Pathology, The University of Auckland

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 MOLECULAR CLOCK REGULATES ANTIBACTERIAL RESPONSES ($156,598 - 2 years) 1120004

2020

Associate Professor Christopher Hall, Associate Professor Guy Warman

Dept. of Molecular Medicine & Pathology, The University of Auckland

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.

PREDICTION OF CARDIOVASCULAR RISKS IN CANCER PATIENTS ($159,944 - 2 YEARS) 1120015

2020

Professor Mark Elwood, Dr Essa Tawfiq, Dr Corina Grey, Dr Matire Harwood, Professor Rod Jackson, Dr Arier Chi Lun Lee, Professor Mark McKeage, Dr Vanessa Selak, Dr Sandar Tin Tin, Dr L. Susan Wells

Epidemiology and Biostatistics, School of Population Health, The University of Auckland

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

LONGITUDINAL ANALYSIS OF AIRWAY MICROBIOTA IN CYSTIC FIBROSIS ($159,003 - 2 years) 1120008

2020

Professor Richard Douglas, Dr Kristi Biswas, Dr Brett Wagner, Dr Mark O'Carroll

Dept. of Surgery, The University of Auckland

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.

DEVELOPMENT OF A CULTURALLY APPROPRIATE WHĀNAU APP FOR SELF-HARM ($158,802 - 2 years) 1120001

2020

Dr Liesje Donkin, Ms Tania Cargo, Associate Professor Sarah Hetrick, Mrs Vartika Sharma

Dept. of Psychological Medicine, The University of Auckland

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.

HIPPOCAMPAL DEFICITS IN AUTISM SPECTRUM DISORDER ($158,373 - 2 years) 1120020

2020

Dr Juliette Cheyne, Associate Professor Johanna Montgomery, Dr Kevin Lee, Dr Yewon Jung

Dept. of Physiology, The University of Auckland

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.

MELANOMA EV-CHIP ($159,937 - 2 years) 1120005

2020

Dr Cherie Blenkiron, Dr Colin Hisey, Professor Cristin Print, Ms Sandra Fitzgerald

Dept. of Molecular Medicine & Pathology, The University of Auckland

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

LYMPHATIC VESSEL GROWTH ($102,034 - 2 years) 1120014

2020

Dr Jonathan Astin

Dept. of Molecular Medicine & Pathology, The University of Auckland

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.

GDM AND SCHOOL AGE OUTCOMES ($159,813 - 2 years) 1120019

2020

Dr Jane Alsweiler, Professor Caroline Crowther, Professor Gavin Brown, Dr Christopher McKinlay

Dept. of Paediatrics: Child and Youth Health, The University of Auckland

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-INDUCED COCHLEAR INFLAMMATION ($159,234 – 2 years) 1119017

2019

Associate Professor Srdjan Vlajkovic, Professor Paul Smith, Professor Peter Thorne

Dept. of Physiology, The University of Auckland

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.

ATP SIGNALLING AND COCHLEAR SYNAPTOPATHY ($108,968 – 2 years) 1119014

2019

Dr Haruna Suzuki-Kerr, Professor Peter Thorne, Associate Professor Srdjan Vlajkovic, Dr Shelly Lin

Dept. of Physiology, The University of Auckland

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.

MEMBRANE DISRUPTION BY CYTOTOXIN AN-58 ($43,526 – 1 year) 1119016

2019

Associate Professor Christopher Squire, Distinguished Professor Margaret Brimble, Associate Professor Adam Patterson, Dr Jeff Smaill, Dr Paul Young, Dr Iman Kavianinia, Dr Iain Hay

School of Biological Sciences, The University of Auckland

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!

CREBRF VARIANT IN BETA-CELL FUNCTION ($159,324 – 2 years) 1119019

2019

Dr Troy Merry, Dr Paul Docherty, Distinguished Professor Geoffrey Chase, Dr Rinki Murphy, Professor Peter Shepherd

Discipline of Nutrition, The University of Auckland

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.

TME STRESS IN HNSCC ($151,615 – 2 years) 1119012

2019

Dr Tet-Woo Lee, Dr Stephen Jamieson, Dr Dean Singleton

Auckland Cancer Society Research Centre, The University of Auckland

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.

UPR IN MPN ($159,999 – 2 years) 1119009

2019

Dr Maggie Kalev, Professor Stefan Bohlander, Dr Dean Singleton

Dept. of Molecular Medicine & Pathology, The University of Auckland

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.

ANTI-CATARACT NANOVESICLE DEVELOPMENT ($158,539 – 2 years) 1119015

2019

Dr Angus Grey, Professor Paul Donaldson, Dr Ilva Rupenthal, Associate Professor Zimei Wu

Dept. of Physiology, The University of Auckland

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.

INVESTIGATION OF LENS PROTEIN FLEXIBILITY ($117,192 – 2 years) 1119018

2019

Dr Nicholas Demarais, Professor Paul Donaldson, Dr Angus Grey, Dr George Guo

School of Biological Sciences, The University of Auckland

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.

MASTERSTROKE ($159,950 – 2 years) 2119013

2019

Dr Doug Campbell, Professor Tim Short, Dr Carolyn Deng, Professor Alan Barber, Professor Chris Frampton

Department of Anaesthesia, Auckland District Health Board

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.

PLACENTAL TOXIN IN PREECLAMPSIA ($159,998 – 2 years) 1119010

2019

Professor Larry Chamley, Dr Torsten Kleffmann, Dr Carolyn Barrett, Associate Professor Katie Groom, Dr Charlotte Oyston

Dept. of Obstetrics & Gynaecology, The University of Auckland

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.

NEUROCARDIAC ARRHYTHMIA MECHANISMS IN LQTS ($156,663 – 1.75 years) 1119006

2019

Dr Annika Winbo, Associate Professor Johanna Montgomery, Professor Jonathan Skinner

Dept. of Physiology, The University of Auckland

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.

MIDODRINE TO PREVENT ORTHOSTATIC INTOLERANCE AFTER HIP AND KNEE JOINT REPLACEMENTS ($159,132 – 2 years) 8119004

2019

Dr Michal Kluger, Ms Monica Skarin, Dr David Rice, Professor Peter McNair

Anaesthesiology and Perioperative Medicine, Waitemata District Health Board

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.

HYALURONAN SIGNALLING & OGD IN THE DEVELOPING BRAIN ($158,403 – 2 years) 1119005

2019

Dr Rashika Karunasinghe, Associate Professor Justin Dean, Professor Janusz Lipski

Dept. of Physiology, The University of Auckland

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.

CENTRAL CHEMOREFLEX IN HYPERTENSION ($159,215 – 1 year 9 months) 1119008

2019

Associate Professor James Fisher, Professor Julian Paton

Dept. of Physiology, The University of Auckland

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.

Each year the Foundation provides funding to support medical research projects for up to two years and a maximum of $160,000. The Foundation is committed to funding excellence and has an established policy of supporting emerging researchers.