Project Grants 2019

June

Neurocardiac arrhythmia mechanisms in LQTS ($156,663 – 1.75 years) 1119006

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

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. 195 words (max 200)

Hyaluronan signalling & OGD in the developing brain ($158,403 – 2 years) 1119005

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.

Central chemoreflex in hypertension ($159,215 – 1 year 9 months) 1119008

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.

The FIIX Study ($152,825 – 2 years) 1119003

Professor Cynthia Farquhar, Dr Sarah Lensen, Dr Lynn Sadler

Dept. of Obstetrics & Gynaecology, The University of Auckland

One in six New Zealand (NZ) women experience a delay in conceiving. Thirty percent of infertile couples have unexplained infertility. Currently women with unexplained infertility in NZ must have tried to conceive for five years prior to a one year waiting list for in vitro fertilisation (IVF). Our research group has recently reported that 30% of women who have three cycles of intrauterine insemination (IUI) will have a live birth. The public funding in NZ allows women to choose four cycles of IUI or one complete cycle of IVF. This study will provide data comparing four cycles of IUI and one complete cycle of IVF allowing women to be fully informed about the best strategy. We will also be considering the impact of 4four cycles of IUI on the subsequent two IVF cycles including cost effectiveness. If we are able to report that four cycles of IUI followed by two cycles of IVF is less expensive than two cycles of IVF then it is likely to have a global impact as then IUI can be offered as an first line alternative to IVF. The information from this study has the potential to influence policy and funding for fertility in NZ and beyond.

Collagen VI knockout ($79,593 – 2 years) 1119001

Dr David Crossman, Dr Carolyn Barrett, Professor Christian Soeller, Professor Peter Ruygrok, Professor Bruce Smaill, Dr David Baddeley, Dr Prasanna Kallingappa

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 contract. This is a serious health condition and a major cause of death of New Zealanders. Through previous research support from Auckland Medical Research Foundation, we have identified collagen VI is likely responsible for damaging the electrical connections responsible for signalling muscle cell contraction. In this project, we will test if removal of collagen VI can be used to prevent damage to these electrical connections and improve cardiac function after myocardial infarction. This will be done by using our state-of-the-art super-resolution microscope to image, at the nano-scale, the structure of these critical electrical connections.

Assessing method agreement in insulin quantification between BioVolt and AUT Roche. ($5,480 – 6 months) 5119007

Dr Catherine Crofts, Mrs Marie Mckay, Dr Amira Hassouna

School of Interprofessional Health Studies, Auckland University of Technology

People with high blood insulin levels have a high risk of developing type 2 diabetes, heart disease, certain cancers or dementia. We want to find a simple test for identifying these people and monitoring whether lifestyle changes can keep their blood insulin levels low and decrease their risk of these diseases. We have access to the BioVolt point-of-care device that will measure insulin levels through a fingerstick blood sample.Before we can use this device, we need to first prove that it is as accurate as the normal laboratory testing processes. We are also concerned that insulin levels in capillary (fingerprick) blood may be different to that in the usual sample of venous blood. We plan to compare the insulin levels between venous and fingerstick blood samples on both the BioVolt device and though normal practices. Once tested, we want to use the BioVolt device in both research and clinical practice to help keep people healthy.

Lactoferrin in prosthetic joint infections ($160,000 – 2 years) 1119002

Professor Jillian Cornish, Dr Simon Young, Dr Scott Bolam, Mr Stuart Irwin

Dept. of Medicine, The University of Auckland

Infection following joint replacement surgery is a devastating complication. It leads to prolonged hospital admissions and poor outcomes for patients and is a heavy economic burden for the health care system. With an aging population and the increased demand for joint replacements, we urgently need to reduce the incidence of infection and improve its treatment. A main challenge of joint replacement infections is the formation of bacterial biofilms on implant surfaces. Once there, the biofilms make the bacteria resistant to antibiotics and the natural defences of the body. This helps the bacteria to gain a foothold in the replaced joint, causing infection that is difficult to eliminate. We have discovered that a novel protein from milk products, lactoferrin, has a natural ability to disrupt bacterial biofilm. This makes them much more susceptible to both antibiotics and the body’s natural defences. Our project will evaluate the effectiveness of lactoferrin for both preventing and treating joint replacement infections. This will be done both in our laboratory and in a rat joint replacement infection model. We have an experienced team of orthopaedic surgeons, microbiologists and molecular biologists who can transfer the knowledge gained in our project from the laboratory to the bedside.

December

Cisplatin-induced cochlear inflammation ($159,234 – 2 years) 1119017

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.

ATP signalling and cochlear synaptopathy ($108,968 – 2 years) 1119014

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

Membrane disruption by cytotoxin AN-58 ($43,526 – 1 year) 1119016

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

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.

TME stress in HNSCC ($151,615 – 2 years) 1119012

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.

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

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.

Anti-cataract nanovesicle development ($158,539 – 2 years) 1119015

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.

Who are the 1M and 1X? ($79,764 – 1 year) 1119011

Dr Daniel Exeter, Dr Katey Thom, Professor Brian McKenna, Dr Anthony O’Brien

Section of Epidemiology & Biostatistics, The University of Auckland

Every day, the New Zealand Police respond to over 100 calls per day from citizens in distress or the whānau. Indeed, mental health is one of the six major demands on police resources, with approximately 280 hours per day of NZ Police time spent on mental health-related calls. While a considerable amount of research has been undertaken to understand the needs of citizens with mental health and addiction challenges from a public health perspective, to-date no studies have considered these from a policing perspective in NZ.This research aims to better understand the socio-demographic context of people in mental distress who have sought support from the NZ Police (NZP) between 2013 and 2019, using a whole-of-population cohort created in Statistics New Zealand’s Integrated Data Infrastructure (IDI).Importantly, all of our data will be de-identified and we will map the geographic patterns of police responses to mental health/addiction (“1M”) or suicidal (“1X”) calls. We also explore whether people in mental distress contacting police (1M/1X) have also sought support for their challenges from relevant publically-funded health and social support services. Working closely with Maori in this research, we aim to improve the health and wellbeing of the 1M/1X population or the coordination of health and social services for those in mental distress, while striving to address ethnic and social inequities.

Investigation of Lens Protein Flexibility ($117,192 – 2 years) 1119018

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.

MASTERSTROKE ($159,950 – 2 years) 2119013

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

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.

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