Awarded Project grants

Project grants awarded 2013

  • 01 Jan 2014

ORAL DEXTROSE GEL FOR PREVENTION OF HYPOGLYCAEMIA IN AT RISK NEWBORN INFANTS – 1113012 ($140,672 – 2 years)

Dr Jane Alsweiler, Prof Jane Harding, Dr Jo Hegarty
Dept of Paediatrics: Child and Youth Health, University of Auckland

Hypoglycaemia (low blood sugar) is the commonest metabolic condition in newborn babies, affecting up to 30% of babies born in Auckland hospitals. It frequently leads to neonatal intensive care unit admission and may cause long-term brain damage. Infants of diabetic mothers are particularly at risk; rates of maternal diabetes have quadrupled in NZ over the last two decades from 2% to 8%, with Polynesian and Maori women having the highest rates. There currently are no evidence-based strategies to prevent hypoglycaemia and its adverse consequences. We have shown that oral dextrose gel is effective in reversing established hypoglycaemia, halving NICU admission rates and improving rates of breastfeeding at two weeks. We now propose a trial investigating the effectiveness of dextrose gel for prevention of hypoglycaemia and its consequences in at risk babies. We will compare two different doses of dextrose gel, given on one or more occasions at feed times to those newborn babies at increased risk of having hypoglycaemia to determine a dose that will best prevent neonatal hypoglycaemia. We will determine whether dextrose gel prevents this common newborn condition with potential long-term health consequences. Such an intervention would revolutionise management of neonatal hypoglycaemia around the world.

 

TARGETING REPLICATION OF A HUMAN RESPIRATORY VIRUS – 1113003 ($139,620 – 2 years)

Dr Esther Bulloch, Dr Richard Kingston
School of Biological Sciences, University of Auckland

Respiratory Syncytial Virus (RSV) is the primary cause of serious respiratory disease in infants. The reported rates of RSV infection in New Zealand are almost twice that of Europe and the USA, and are particularly high for the Maori and Pacific Island population. There is no vaccine that prevents RSV infection, nor any effective therapy to treat infected individuals. We seek to understand how RSV replicates within human cells. RSV has complex replication machinery that creates the blueprint for new viral proteins, messenger RNA (mRNA), as well as copying the entire viral genome. However, the virus lacks a protein production system for translating viral mRNA into viral proteins, so it co-opts the system of the human host cell. For the viral mRNA to be processed by the host cell it must have specific chemical modifications. RSV and related viruses have unusual enzymes integrated into their replication machinery that carry out these mRNA modifications. We will isolate these enzymes using a technology developed in our laboratory, and carry out the first detailed molecular studies of their activity. The long-term goal is to develop new anti- viral agents that prevent RSV replication by targeting its unique mRNA modifying enzymes.

 

DANGEROUS DEBRIS – 1113002 ($139,447 – 18 months)

Prof Larry Chamley, Dr Qi Chen
Dept of Obstetrics & Gynaecology, University of Auckland

Preeclampsia affects approximately 3000 New Zealand women and their babies annually. Preeclampsia causes potentially life-threatening high blood pressure in the mother and often requires the premature delivery of the baby to prevent the death of the mother or baby. Something from the placenta triggers preeclampsia but we do not know exactly what this is. We have evidence that dead cells from the placenta called syncytial nuclear aggregates may be this trigger but only if they died by a process called necrosis. We also have evidence that antiphospholipid autoantibodies, that are found in some women with preeclampsia, cause syncytial nuclear aggregates to die by necrosis. Why death by necrosis is so important in developing preeclampsia is unclear but this may be because necrotic syncytial nuclear aggregates display molecules called danger signals which cause mum’s blood vessels to tighten leading to the high blood pressure of preeclampsia. We will investigate whether antiphospholipid antibodies cause syncytial nuclear aggregates to display danger signals and whether syncytial nuclear aggregates from preeclamptic pregnancies display danger signals. Ultimately our goal is to understand how necrotic syncytial nuclear aggregates affect blood vessels and armed with that knowledge, we hope to improve treatments for women affected by preeclampsia.

 

REGULATION OF CREATINE SYSTEM IN NEURONS – 1113024 ($165,713 – 2 years)

A/Prof David Christie, A/Prof Nigel Birch
School of Biological Sciences, University of Auckland

This is produced by mitochondria, organelles that act as the power generator. Many neurodegenerative diseases have an energy deficit due to a loss of mitochondrial function. As a result, agents that promote mitochondrial activity have the potential to protect neurons. Creatine, a commonly used dietary supplement, is one such molecule as it enhances and maintains cellular energy levels. To be effective creatine must first be taken up into neurons and then be converted to phosphocreatine. These processes require a group of creatine system proteins. In this research we will investigate how the levels of creatine system proteins are controlled and how they contribute to the energy levels and function of neurons. If ways can be found to up-regulate creatine system proteins this may lead to new strategies to enhance the neuroprotective effects of creatine for the treatment of human neurodegenerative diseases.

 

ANTIMALARIAL CONJUGATES – 1113004 ($23,600 – 2 years)

A/Prof Brent Copp, Dr A Norrie Pearce
School of Chemical Sciences, University of Auckland

Malaria is a parasitic disease that has re-emerged as a growing human health hazard in the past few decades, affecting millions of people in Africa, Asia and South America. The drugs that are available for the treatment of malaria are becoming increasingly inadequate because of resistance and lack of patient compliance for multidrug treatment regimes. New, more efficient medications are urgently needed. We have recently discovered a class of natural products that exhibit moderate antimalarial activity and which when synthesised and modified in certain ways yield drug candidates that effectively kill malaria in mammals. This project involves the synthesis and biological evaluation of new molecules based around our discovery, where we will optimize the parasite killing power of our current antimalarial while at the same time reducing the cost of its large scale manufacture. Our so-called multimodal antimalarials will provide proof of concept of combining therapeutics that kill and prevent reinfection with malaria into a single drug compound that not only is effective at disease treatment but also avoids resistance mechanisms and enhances patient compliance.

 

STUDIES OF THE EARLIEST EVENTS OF ALZHEIMER’S DISEASE IN THE ADULT HUMAN BRAIN – 1113025 ($114,416 – 2 years)

Dr Maurice Curtis, Prof Richard Faull
Centre for Brain Research, University of Auckland

Alzheimer’s disease (AD) causes severe memory loss and progressive dementia that directly affects 48,000 people in New Zealand and has a significant impact on the lives of a further 300,000 people in New Zealand. What causes this devastating disease is currently unknown in most instances with only approximately 10-15% of cases having an obvious genetic susceptibility. In brains affected by AD there is major cell death in the temporal and frontal lobes, however 8-10 years before this is evident the olfactory system (the smell centre) has already suffered significant cell death. To overcome the problem of major cell loss in AD, it will be important to intervene early before major cell loss has occurred but to date the major studies of AD have focussed on end stage disease and not the initial brain changes. In the current project we aim to study the human olfactory system (where the disease begins), to determine what cell type are affected the most and to compare it with the textbook regions where damage occurs in AD. We will identify the earliest changes that occur in AD in the hope that future treatments might be helpful before depletion of brain cells has occurred in the brain.

Funded by: W & W A R Fraser Fund

 

URATE AND BONE – 1113015 ($157,475 – 2 years)

A/Prof Nicola Dalbeth, Dr Jacquie Harper, Prof Jillian Cornish
Dept of Medicine, University of Auckland

Elevated urate levels in the blood are present in approximately 20% of the adult population. Recent observational studies have reported that high urate levels are protective in the development of thin bones (osteoporosis) and fractures. This laboratory study aims to understand how urate exerts this protective effect. We will study the effects of urate on the function of bone-forming cells (osteoblasts) and cells that control the breakdown of bone (osteoclasts). We will also study the effects of medications that reduce urate levels on bone structure. If urate does indeed directly act on bone cells to increase bone density and reduce fracture risk, these observations may have important clinical implications in guiding blood urate targets in people treated for gout (the most common form of inflammatory arthritis), understanding patterns of bone disease in people with gout, and, in the long-term, identifying new therapeutic strategies for prevention of osteoporosis.

 

MYELINATION FAILURE IN THE PRETERM BRAIN – 1113021 ($114,433 – 2 years)

Dr Justin Dean
Dept of Physiology, University of Auckland

The white matter regions of the brain are important for transferring signals between different brain structures. For rapid movement of these brain signals, cells in the white matter called oligodendrocytes produce an insulating material called myelin. In preterm born babies, oligodendrocytes show a particular vulnerability to injury resulting from low brain blood flow, leading to loss of myelin and cerebral palsy, a devastating lifelong movement disorder for which there is no cure. Therefore, there is a need for new therapies. In humans, although oligodendrocytes are easily killed, we now know that they rapidly grow back. Strikingly, for unknown reasons these new oligodendrocytes fail to properly mature, and do not produce myelin, in areas of injury. We have new evidence that a molecule called hyaluronan is highly up-regulated in preterm ischemic white matter injury, and that hyaluronan may be the cause of failure of oligodendrocytes to produce myelin. In this proposal, we will examine how hyaluronan triggers myelin deficits in the preterm brain. This new knowledge will further our understanding of the causes of cerebral palsy in preterm infants, and determine whether blocking hyaluronan is a potential treatment strategy in this large group of children.

 

DIABETIC CATARACT – 1113006 ($59,061 – 18 months)

Prof Paul Donaldson, Miss Irene Vorontsova
School of Medical Sciences, University of Auckland

Cataract occurs earlier in patients with diabetes, and is associated with a higher rate of surgical complications. Due to the increasing incidence of diabetes, a cataract epidemic is looming that will place an economic burden on the health system. Research efforts to alleviate this burden have focused on finding alternative medical therapies to delay cataract progression and reduce the need for surgery. The Molecular Vision Laboratory at the University of Auckland has shown that dysfunction in the ability of lens to regulate cell volume is an underlying cause of diabetic cataract. On-going work by the Auckland group has identified the key membrane transport proteins that effect changes in lens cell volume. More recently a PhD student in the laboratory, Irene Vorontsova, has identified the regulatory machinery that modulates the activity of these transporters and which therefore ultimately determine the transparency of the lens. Ms Vorontsova is a former recipient of the AMRF’s Senior Scholarship and in this current application funds are requested to continue Ms Vorontsova’s work into how these regulatory pathways are disrupted in the diabetic lens. This work will determine whether these regulatory pathways are potential targets for development of therapies to combat the diabetic cataract epidemic.

Funded by: The Hugh Green Diabetes & Breast Cancer Research Fund

 

THE TUI STUDY – 1113008 ($78,500 – 2 years)

Prof Cindy Farquhar, Dr Emily Liu, Miss Nicola Arroll
Dept of Obstetrics & Gynaecology, University of Auckland

Up to 20% of New Zealanders will experience infertility at some point in their lives. The TUI study aims to evaluate the effectiveness of a fertility treatment called intrauterine insemination (IUI) with stimulation. IUI is especially popular in New Zealand as couples with unexplained infertility cannot access the publicly funded fertility clinics unless they have been infertile for five years. As a result many women decide to pay for one to two cycles of stimulated IUI while they are waiting to meet the criteria for public funding. IUI with ovarian stimulation involves the women taking medication to stimulate ovulation before introducing sperm directly into the uterus in the hope of aiding conception. Currently knowledge around the effectiveness of this treatment in women with unexplained infertility and low chance of pregnancy (less than 30% chance) is not extensive. If this randomised controlled trial demonstrates that intrauterine insemination with stimulation is effective then this would provide evidence for a less invasive and cost effective alternative to In vitro fertilisation for women with unexplained infertility.

 

CB2 IN THE DISEASED HUMAN BRAIN – 1113011 ($66,792 – 1 year)

A/Prof Michelle Glass, Dr Scott Graham
Dept of Pharmacology, University of Auckland

Cannabinoid CB2 receptors have been suggested to be an appealing target for neuroinflammatory disorders as many believe them to be found only on immune cells. However, their distribution is actually highly controversial with some groups reporting wide spread neuronal distribution, while others see little evidence for CB2 in the brain. Part of the reason for these discrepancies is that the antibodies used to detect this protein are not entirely specific. Furthermore, many of the assumptions about CB2 expression in the brain are based on animal studies and may not represent the situation in the human brain. As many drug companies are aiming to bring CB2 directed therapies onto the market it is critical that the localisation of the receptor be accurately determined. We have recently developed a sensitive method for determining the expression of CB2 in the normal healthy brain, which we now wish to apply to disease brains from the Human Brain Bank.

 

ACELERATED BEP STUDY – 2113019 ($59,105 – 2 years)

Dr Fritha Hanning, Dr Peter Fong, Dr Reuben Broom
Auckland Regional Cancer & Blood Service, Auckland City Hospital

Testicular cancer and closely related cancers called germ cell tumours are the most common cancer in men aged 16 to 45. Despite this, it receives very little attention or publicity, in part due to an understandable reluctance of men in this age group to discuss their cancer journeys. Thankfully for those men who are able to detect their cancer early, there are excellent outcomes with treatment ranging from 98-99% cure rates for men with stage one disease (confined within the testicle) to 90-95% for men with good prognosis metastatic cancer (cancer which has spread to other parts of the body). Unfortunately for men whose disease is more extensive and aggressive, there is still a significant chance of dying from the cancer. The research study ‘Accelerated BEP’ aims to improve outcomes for men whose cancer was not diagnosed before it reached this more serious stage. It is looking at whether changing the timing of an established chemotherapy treatment will improve survival. A positive outcome from this study would mean an increased cure rate for this group of young men and an increased chance of them living full and productive lives.

Funded by: Sir Lewis Ross Fund and the Rose Richardson No. 1 Trust

 

REDUCING FGF23 IN CHRONIC KIDNEY DISEASE – 3113014 ($133,166 – 1 year)

Dr Christopher Hood, Mr Mark Marshall, Dr Joanna Dunlop
Renal Dept, Middlemore Hospital

Chronic kidney disease (CKD) is a major public health issue which is both very common and harmful, with a similar magnitude of effect as diabetes. This is mainly due to greatly increased levels of cardiovascular disease (CVD) in CKD patients. Recent ground-breaking research has identified a causative pathway linking CKD and CVD, via increased levels of a hormone called FGF23. FGF23 acts directly on the heart to cause enlargement of heart cells, which results in cardiac failure and increases the risk of sudden cardiac death. Multiple research efforts attempting to reduce FGF23 levels in CKD all use intensive hospital-based treatments of specialised diets or treatment regimens unsuited to widespread “real world” use. Our study aims to demonstrate that a simple treatment with niacinamide (a metabolite of vitamin B3) will significantly reduce FGF23. Such a simple treatment could transform the field, taking it away from clinical trials and specialist clinics to a primary care-based intervention, applicable to the wider CKD population. Our trial aims to investigate whether FGF23 is reduced by niacinamide treatment. A successful result would support larger studies aimed at demonstrating that niacinamide can prevent the cardiac enlargement and increased cardiovascular disease seen in people with CKD.

 

TROPHOBLAST STEM CELLS – 1113005 ($50,000 – 18 months)

Dr Jo James, Prof Larry Chamley
Dept of Obstetrics & Gynaecology, University of Auckland

The placenta is the baby’s life-support system in utero, and its formation and function in early pregnancy is crucial for pregnancy success. Inadequate placental development results in pregnancy disorders from conception to birth including miscarriage, preeclampsia (high blood pressure in pregnancy) and intrauterine growth restriction (small babies), which together affect around 15,000 pregnancies in NZ each year. Despite its importance, we understand very little about how it the human placenta develops. This research aims to address this problem by studying the stem cells from which the placenta is formed. The placenta is composed of specialised cells called trophoblasts, which form different populations each critical for pregnancy success, but we do not understand how these populations arise. We have isolated cells that are likely to be trophoblast stem cells from early placental samples, and are characterising these cells in order to develop trophoblast stem cells for use in the laboratory. This will allow us to study what regulates the formation of different trophoblast populations. This research will help us identify potential underlying causes of pregnancy disorders and may lead to new therapies for pregnancies with poor placentas.

 

EFFECTS OF PARKINSONIAN TOXINS ON THE LOCUS COERULEUS – 1113007 ($103,000 – 2 years)

Prof Janusz Lipski, Mr Andrew Yee, Dr Peter Freestone, Dr Ji-Zhong Bai
Dept of Physiology & Centre for Brain Research, University of Auckland

Parkinson’s disease (PD) is one of the most common degenerative brain disorders leading to motor deficits such as tremor in hands, slowness of movement, muscle stiffness and gait disturbance. Importantly, PD patients also suffer from debilitating non-motor symptoms, such as sleep disturbance, cognitive and mood disorders and dysfunction of the cardiovascular system, bowel and bladder, which cause additional disability and severely impact the quality of life of those affected with PD. Previous research indicates that at least some of these non-motor symptoms are due to degeneration of nerve cells in the Locus Coeruleus (LC), but the cellular mechanism of this damage is not known. Remarkably, degeneration of the LC can exceed damage of the Substantia Nigra pars compacta (SNc) associated with the ‘classical’ motor symptoms of the disease. Our study, conducted on isolated animal brain tissue, will test and compare the effects on LC neurons of two environmental toxins/pesticides which have been implicated in the pathogenesis of some cases of PD: rotenone and MPP+. We will also compare the effects evoked in LC neurons with the responses induced in SNc neurons, and a further group of neurons which is not affected in PD. This research will advance our understanding of the mechanisms of action of parkinsonian toxins on neurons vulnerable in PD, and should help to elucidate the complex relationship between the motor and non-motor symptoms in this debilitating disorder.

Guardian Trust

Funded by: Angus Family Trust

 

SHON RECEPTOR IDENTIFICATION – 1113022 ($159,960 – 2 years)

Dr Dong-Xu Liu, Dr Christopher Squire
Liggins Institute, University of Auckland

Breast cancer is a major health issue, being the most common malignancy and the leading cause of cancer deaths among New Zealand women. Each year approximately 3,000 women are diagnosed with breast cancer and more than 650 die from the disease. We have identified a novel secreted oncoprotein, called SHON, in the blood. SHON plays an important role in breast cancer. Its expression status in breast tumours predicts the response of patients to anti-oestrogen therapies. We will identify the mechanism by which SHON regulates cellular function by finding proteins to which it binds and signalling pathways that it activates. These studies will provide an important contribution to our understanding in the area of secreted oncogenic proteins and is likely to lead to better treatment for breast cancer in the future.

Funded by: Breast Cancer Research Fund

 

LONG QT SYNDROME AND HYPERTROPHIC CARDIOMYOPATHY GENE ANALYSIS 2113017 – ($50,000 – 18 months)

Dr Donald Love, Dr Jonathan Skinner, Dr Ivone Un San Leong
Diagnostic Genetics, LabPlus

Congenital long QT syndrome and hypertrophic cardiomyopathy are life-threatening cardiac disorders that are the most common causes of sudden death in 1 – 40 year olds in New Zealand, with an incidence of 1 in 4,500 and 1 in 500, respectively. These diseases commonly present in childhood and young athletes, and are characterised by unexplained fainting episodes and dangerously fast heart rates that could cause sudden death. The genotyping of patients with these disorders has greatly assisted both with family screening and individualizing clinical management. The current sequence-based screening strategy for mutations in patients is labour intensive. Critically, developments in Massively Parallel Sequencing (MPS) technology has made it possible to screen scores of genes for mutations, or the entire coding potential of the human genome (termed whole-exome sequencing, WES), in parallel. This project will establish MPS technology in the clinical diagnostic arena of New Zealand (with a focus on cardiac disorders), and will therefore improve the current method and provide an enhanced national service for patients.

 

TECHNOLOGY AND CARDIAC REHABILITATION – 1113020 ($153,003 – 2 years)

A/Prof Ralph Maddison, Dr Robyn Whittaker, Dr Anna Rolleston, Hon Prof Ralph Stewart, Dr Nicholas Grant, Dr Ian Warren, Mr Jonathan Rawstorn
National Institute for Health Innovation, School of Population Health, University of Auckland

Exercise is essential to aid recovery from a heart attack; however adherence to regular exercise is low. In this trial we will compare the effectiveness of home-based monitored exercise using mobile phones and monitoring technology to existing supervised exercise cardiac rehabilitation. 230 participants will be allocated at random to 12 weeks standard supervised exercise cardiac rehabilitation or to the new mobile phone programme. Assessments will compare physical fitness, and change in risk factors associated with heart disease between the two groups. This approach has potential to improve the delivery of cardiac rehabilitation services in New Zealand for those who need it.

Funded by: AC Horton Estate

 

OXYGEN IN DISEASE KIDNEYS – 1113016 ($160,000 – 2 years)

Prof Simon Malpas, Dr Maarten Koeners
Dept of Physiology, University of Auckland

Kidney disease is a growing global public health problem. Low tissue oxygen and kidney disease are associated although the mechanisms responsible and their time course are ill-defined. We hypothesize that low oxygen levels in the kidney is central in the pathogenesis of kidney disease. This project will examine how and when low oxygen levels in the kidney can play a major role in driving disease progression and whether improving kidney oxygenation can prevent kidney disease. Investigation of kidney oxygen regulation has been hindered because of an inability to measure tissue oxygen for long periods of time. Using our world first technology which allows wireless measurement of kidney tissue oxygen in unrestrained rats we have solved this problem. We will investigate, using this technology and unique expertise, the sequence of events that lead to reduced kidney tissue oxygen in kidney disease. We aim to identify when and which mediators/controllers of long-term regulation of kidney oxygen precedes and/or is a prerequisite for the progression of disease. This will reveal causation that will assist in optimising the appropriate, and novel, treatment strategies. We believe this will ultimately have a major impact in clinical practice, making it a very promising and timely subject.

 

REVERSAL OF MULTI-DRUG RESISTANCE BY DRUG-PHYTOCHEMICAL COMBINATION THERAPY – 1113026 ($159,293 – 2 years)

A/Prof James Paxton, Dr Zimei Wu, Dr Yan Li
Dept of Pharmacology & Clinical Pharmacology, University of Auckland

A major factor responsible for the failure of chemotherapy in pancreatic cancer is the development of multi-drug resistance due to up-regulation of various efflux pumps in the cancer cells. The latter can efficiently remove the drug from the cell, thus causing the drug to lose its effect. Our aim is to investigate a novel bi-functional liposomal delivery system which contains the anticancer drug plus curcumin, an inhibitor of the efflux pump. This combinational liposome will more effectively target and retain the active drug within the cancer cell, thus overcoming multidrug resistance, and also minimising any toxic side effects.

 

IMPROVING THE SURGICAL DRAINAGE OF NECROTISING PANCREATITIS – 1113013 ($28,761 – 2 years)

Dr Anthony Phillips, Prof John Windsor, Dr Harvey Ho, Dr Lisa Brown
School of Biological Sciences, University of Auckland

Acute pancreatitis is due to inflammation of the pancreas gland. This can develop into avery severe form in which a portion of the pancreas gland dies and becomes infected. This has a high mortality for patients, and is best treated by draining the area of infection by passing a drain through the skin into the dead, infected pancreatic tissue. Unfortunately, these drains work in less than 50% of patients and regularly block with the pancreatic tissue, requiring patients to undergo a major open operation to remove the dead tissue, which increases the risks of complications and death. This research aims to reduce the occurrence of drain blockage, by finding an enzyme solution that could be flushed down the drains to dissolve the pancreatic tissue. There is also the opportunity to improve drain design to keep it open and to make it easier to drain the infected tissue. The optimization of the drainage of infected pancreatic tissue will reduce the burden of this disease on patients, reduce the requirement for major open surgery, and reduce costs to the health system.

 

MAGGOT SECRETIONS PROMOTE WOUND HEALING? – 1113023 ($28,761 – 1 year)

Dr Anthony Phillips, Dr Cherie Blenkiron
School of Biological Sciences, University of Auckland

The use of maggots for a medicinal purpose is age-old. The maggots, from the green bottle blow-fly, secrete a potent cocktail of molecules which kill infecting bacteria, digest away dead tissue and even directly promote wounds to heal. We intend to look at the activity of maggot secretions on a range of target cells to give us a greater understanding of its biological effects. With better understanding of its bioactivity we hope to exploit specific components for use in the clinic as new classes of treatment for a range of surgical wounds.

 

Gcn2 INTERACTOME – 4113010 ($66,630 – 2 years)

Dr Evelyn Sattlegger, Miss Su Jung Lee
Institute of Natural and Mathematical Sciences, Massey University

The enzyme Gcn2 is involved in many life-affirming biological functions, such as proper food selection, viral defence, memory, and overcoming stress and starvation. Consequently, Gcn2 is a highly relevant protein, for medicine especially as research has linked Gcn2 to various diseases/disorders such as aberrant feeding behaviour, Alzheimer’s, cancer, and impaired viral defence. Given that these diseases/disorders significantly impact on health and quality of life, this underscores the need to find drugs for their treatment. However, in order to prevent unwanted side effects, measures are necessary that only treat the specific Gcn2 function that went awry. For this we first need to fully understand how Gcn2 is kept in check in the cell. Although Gcn2 is a topic of research world-wide, there remains one significant knowledge gap central to understanding Gcn2 function: the comprehensive identification of proteins that bind to Gcn2, and thereby control Gcn2. These proteins are promising targets for pharmaceutical treatments to modify specific Gcn2 functions that lead to a particular Gcn2-associated disease/disorder. The PI’s research team is in a unique position to identify these Gcn2 binding proteins, and to spearhead the first characterisation of these proteins, as the relevant experimental procedures have been established in her lab.

 

THE NEUROPHYSIOLOGICAL BASIS OF THE ADAPTATION LEVEL THEORY OF TINNITUS – 1113028 ($85,508 – 1 year)

Dr Grant Searchfield, Prof Dirk De Ridder, Dr Cathy Stinear, Prof Ian Kirk, Mr Giriaj Singh Shekhawat
School of Population Health, University of Auckland

Tinnitus (“ear and head noise”) is a highly prevalent condition affecting approximately 15% of the population. Severe tinnitus can lead to disruption of work, social activities and sleep; and lead to anxiety and depression. There is a pressing need for effective therapies to help solve this common problem. In the last decade there have been tremendous advances in our understanding of the mechanisms underlying tinnitus but effective treatments for tinnitus remain elusive despite these advances in knowledge. Tinnitus can be temporarily reduced or eliminated by sound stimulation and non-invasive brain stimulation but only in some people, some of the time. Tinnitus is complex; studies of brain activity indicate auditory, memory, attention and emotional parts of the brain work together to create tinnitus. These studies have led to a “Neurophysiological network” model of tinnitus. Recently an “Adaptation Level Theory” model of hearing has explained how memory, attention and emotion might contribute to tinnitus magnitude. The proposed research will examine how the two models of tinnitus interrelate. We will measure brain activity (Electroencephalography, EEG) and tinnitus loudness before, during, and after sound stimulation and non-invasive stimulation of different brain areas. The studies should identify new targets and means for treating tinnitus.

Guardian Trust

Funded by: Jean Cathie Research Fund

 

CANNABINOID DRUGS FOR THE TREATMENT OF TINNITUS – 7113027 ($80,976 – 1 year)

Prof Paul Smith, Dr Yiwen Zheng
Dept of Pharmacology and Toxicology, University of Otago

Tinnitus is a debilitating neurological disorder in which a person hears sounds that do not physically exist. Approximately 7% of the New Zealand population is estimated to suffer from tinnitus at least 50% of the time and the condition becomes more prevalent with age. Tinnitus substantially reduces the quality of life, resulting in an inability to concentrate and increased anxiety. Approximately 50% of tinnitus sufferers also suffer from depression. Unfortunately, there are few effective treatments. We have shown that receptors in auditory brain regions for chemicals known as ‘cannabinoids’, undergo changes during tinnitus. We therefore propose to test whether a cannabinoid drug known as ‘Sativex’, might be beneficial in the treatment of the disorder. First, we will determine whether it reduces the perception of tinnitus. Second, we will measure the way in which it alters brain activity in the brain regions which normally exhibit increased excitability during tinnitus. Since Sativex is already available for prescription in New Zealand, if we obtained evidence indicating that it could be useful in the treatment of tinnitus, this drug could potentially be used with a minimal delay.

Guardian Trust

Funded by: Jean Cathie Research Fund

 

THE SYNAPTIC BASIS OF AUTISM – 1113018 ($21,048 – 1 year)

Dr Charlotte Thynne
Dept of Physiology & Centre for Brain Research, University of Auckland

Autism Spectrum Disorders are complex disorders that are diagnosed based on behavioural symptoms including social and cognitive impairments, communication difficulties and repetitive behaviours. Interestingly, many of the genes that have been implicated in Autism encode proteins found at excitatory synapses in the brain. These include genes which encode postsynaptic scaffolding proteins as well as presynaptic calcium channels and calcium dependent mechanisms. This work aims to determine if there is a functional sub-cellular link between postsynaptic scaffolding proteins and presynaptic calcium channels, which could explain the shared features observed in Autism patients carrying mutations in the genes which encode these separate entities. Using electrophysiology techniques, I will examine how ProSAP2, a postsynaptic scaffolding protein implicated in Autism, regulates presynaptic calcium channel function and how autism-associated mutations in this protein affect this regulation. These experiments have the potential to determine how the function and plasticity of excitatory synapses may be disrupted in Autism, leading to interference with cognitive function and behaviour.

 

GENETICS OF ANTERIOR CORNEAL DYSTROPHY – 1113001 ($138,968 – 18 months)

Dr Andrea Vincent, A/Prof Trevor Sherwin, Prof Phil Crosier
Dept of Ophthalmology, University of Auckland

Inherited disorders affecting the clear front window of the eye are known as corneal
dystrophies. Members of a unique NZ family have significant recurrent episodes of eye pain from childhood, caused by the front surface of the cornea falling off, which often leads to progressive scarring. The cause of this rare disease is unknown, however our recent work shows this disease is due to one of two gene mutations on chromosome 10. Our aim is to understand the normal role of these genes, and the consequence of changes to these genes, in corneal health and disease. We will look at the two protein products of these genes in donor corneas to establish where the proteins sit within the outer-most layer of corneal cells, and what stimuli, e.g. stress or trauma, may change their production. We will then establish disease models in zebrafish by introducing the disease gene(s) into the developing zebrafish embryo, to see the effect on the zebrafish cornea. Using this animal model of a rare genetic disorder will help identify an underlying cause for a more common condition, recurrent corneal erosion, and will help target effective treatments for corneal wound healing, both accidental, and due to surgical interventions.

 

HOMING IN ON THE EPITOPE TARGETS FOR NR1 ANTIBODIES – 1113009 ($138,076 – 2 years)

A/Prof Deborah Young
Dept of Pharmacology, & Clinical Pharmacology, University of Auckland

The NMDA receptor in the brain plays an important role in functions such as learning and memory. Over-activation or dysfunction of the NMDA receptor that occurs in certain neurological diseases causes neuronal cell death or can affect learning and memory making this receptor a key target for therapies. Traditional NMDA receptor blockers that aim to prevent the deleterious effects associated with NMDA receptor dysfunction are associated with adverse side-effects in humans which limits their usefulness. We have shown that antibodies to the NR1 subunit of the NMDA receptors can alter the function of NMDA receptors leading to improved learning and memory, and resistance to experimentally-induced brain insults in rats. Anti-NMDA receptor encephalitis, a disease associated with seizures and memory loss in humans is mediated by NR1 antibodies that could be binding to a region of the NR1 protein that is different to our cognitive-enhancing and protective NR1 antibodies. Here, we use rat models to help distinguish the parts of the NR1 subunit important for generating NR1 antibodies that produce beneficial and detrimental effects on cognition and neuroprotection. These results will contribute to the development of a new class of safe therapies applicable for a broad range of neurological conditions.

More Awarded Project grants
Awarded Project Grants 2018
Project Grants Awarded 2017
Image courtesy of Ponsulak / FreeDigitalPhotos.netProject grants awarded 2016
Project grants awarded 2015
Project grants awarded 2014
Project grants awarded 2012