Dr William Abbott
Liver Transplant Unit, Auckland District Health Board
A chronic hepatitis B virus (HBV) infection carries a high risk of developing liver cancer. This risk is particularly high in patients who have a viral protein in their blood called the hepatitis B virus ‘e’ antigen (HBeAg). One of the primary goals of current HBV treatment is to stop production of HBeAg in the liver, as this reduces the risk of liver cancer. Unfortunately, most patients do not permanently clear the HBeAg on treatment, and new therapeutic strategies to suppress HBeAg production are needed. There is a natural mechanism by which some patients abrogate HBeAg production known as HBeAg seroconversion. It results from the accumulation of mutations in the viral DNA that stop HBeAg production. The mechanisms that drive accumulation of these mutant viruses are unknown. One possibility is that the intracellular innate immune system, which exists within all cells, recognises the HBeAg and suppresses it’s production. The purpose of this project is find evidence that the intracellular innate immune system interacts with the HBeAg. This will give clues to the mechanisms that naturally suppress HBeAg production and provide targets for development of new treatments.
FUNDED BY: John and Poppy Stilson Endowment Trust
A/Prof Rohan Ameratunga, A/Prof Klaus Lehnert, Dr Euphemia Leung, Se See-Tarn Woon
Virology and Immunology, Auckland District Health Board
Common Variable Immunodeficiency disorder (CVID) is the most prevalent symptomatic primary immunodeficiency that requires medical intervention. Up to 20% of non‐consanguineous families have two or more affected first degree relatives. In spite of this, the causative genetic defects have not been identified in the majority of patients with CVID. With the assistance of our previous AMRF grant, we have applied modern genome‐wide approaches to unravel the genetic basis of CVID in a family. Our hypothesis was that another gene was involved in the pathogenesis of CVID in this family. We have identified a second nonsense mutation in the TCF3 transcription factor (T168fsX191), which is likely to contribute to the phenotypic presentation in this family. This is potentially one of the best examples of digenic inheritance in humans and may be proof of concept that epistasis could play an important role in the pathogenesis of CVID. We request funding to identify the pathological mechanisms responsible for the CVID-like phenotype in this family.
FUNDED BY: AC Horton Estate
Dr Askarian-Amiri, Dist. Prof Bruce Baguley, Dr Graeme Finlay
Auckland Cancer Society Research Centre, University of Auckland
Breast cancer is the third most common cancer in New Zealand and its treatment is still a major challenge. There is a great need to better understand the molecular mechanisms underlying its pathogenesis, so as to allow the development of improved therapies. Many genetic factors are known to be involved in breast cancer progression, and in the last decade, the role of epigenetic factors have been implicated. Epigenetic changes do not involve DNA sequences but arise when chemical tags in the DNA environment affect gene expression and cause cellular and physiological variations. We are studying one epigenetic mechanism that may regulate the ability of ribosomes to select particular messenger RNA molecules for use in protein synthesis in breast cancer cells. We anticipate that these findings will shed light on novel mechanisms that regulate the production of proteins at ribosomes, will reveal mechanisms of cancer development, and will provide us with potential targets for new therapies in breast cancer.
Dr David Barker, Dist. Prof Bill Denny, Dr Johannes Reynisson
School of Chemical Sciences, University of Auckland
Recently it has been discovered that thieno[2,3‐b]pyridines have high efficacy against a range of human tumour cell lines in particular triple negative breast cancer cells, which are particularly difficult to treat in the clinic. These compounds were found to target phospholipase C (PLC) a protein involved in crucial cellular processes namely, growth factor induced cell motility and cell adhesion. The compounds also sensitize cancer cells and improved the activity of other clinically used cancer treatments. Previous thieno[2,3‐b]pyridines were however poorly soluble and this limited their therapeutic use. The aim of this project is to prepare new compounds similar to the thieno[2,3‐ b]pyridines which have increased solubility under physiological conditions. The new compounds will be prepared using a combination of molecular modelling, advanced synthesis and then tested using an array of sophisticated biological assays. We believe it is possible to introduce a whole new therapeutic dimension to cancer treatment based on the inhibition of PLC.
Dr Carol Chelimo, A/Prof Merilyn Hibma, Prof Suzanne Garland, Prof Thomas Lumley – 1115005 ($151,243 – 2 years)
Dept of Obstetrics and Gynaecology, University of Auckland
Squamous cell oropharyngeal cancers (OPCs) have been linked to human papillomavirus (HPV) infection. Oropharyngeal cancers affect the oropharynx, tonsil and base of the tongue. A rapid rise in squamous cell OPCs has been observed, mainly among males, in New Zealand (NZ) and several high‐income countries. However, there is lack of data on the prevalence of oral HPV infection in NZ, and conclusive evidence is lacking on determinants of oral HPV infection. To address this, we will undertake a population‐based study to provide NZ‐specific estimates of oral HPV prevalence in males and females aged 18‐64 years residing in the Auckland Region. We will also determine which factors are associated with oral HPV infection, and whether females who have been vaccinated against HPV have a lower oral HPV prevalence. Findings from this study will likely have clinical and public health implications. It will provide a better understanding of the rising incidence of OPC in NZ males and information that would be useful in implementing strategies to prevent HPV‐related oral cancers (such as, extending HPV vaccination to males).
FUNDED BY: Pauline Gapper Charitable Trust
Dr Qi Chen, Dr Katie Groom Prof Larry Chamley, Prof Peter Stone
Obstetrics and Gynaecology, University of Auckland
Preeclampsia is a human pregnancy specific disorder which affects 3-5% of pregnancies. There is no effective treatment except delivery of the placenta/fetus. While the pathogenesis of preeclampsia is unclear, it is known that this disease is triggered by a toxic factor(s) released from placenta. Trophoblastic debris may be one such factor. Trophoblast debris is shed from the placenta into the maternal blood in all pregnancies but there is increased trophoblastic debris shed from placenta in preeclampsia and this debris is toxic causing endothelial cell activation. We reported that antiphospholipid antibodies, a strong risk maternal factor of preeclampsia, increased the amount of toxic trophoblastic debris shed by disrupting mitochondria. We believe this results in increase oxidative damage with disruption of cell death pathways leading to increased shedding of trophoblast debris. We recently also reported that the trophoblast debris produced by normal placentae treated with preeclamptic sera toxic and activates endothelial cells. Melatonin is a lipid soluble molecule produced by the ovary and placenta that has antioxidant effects and which may have beneficial effects in preeclampsia. In this proposal, we will investigate whether melatonin can reverse the effects of preeclamptic sera or antiphospholipid antibodies on placental oxidative damage and the production of toxic trophoblastic debris.
Dr David Crossman, Prof Peter Ruygrok, Mr Maximilian Pinkham, Dr Mia Jullig, Dr Christian Soeller, Dr Carolyn Barrett
Dept of Physiology, University of Auckland
Human heart failure is the inability of the heart to pump enough blood to meet the energetic demands of the body. 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 that an unusual collagen is responsible for damaging the electrical connections in charge of signalling muscle cell contraction. In this project we will test if an anti-fibrotic drug therapy can be used to prevent damage to these electrical connections and improve function in ischemic heart failure. 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. The potential is to confirm a previously unrecognised mechanism of heart failure and identify a new target for future treatments.
FUNDED BY: T. M. Hosking Charitable Trust
Prof Nicola Dalbeth, Prof Jillian Cornish, Dr Ashika Chhana
Dept of Medicine, University of Auckland
Gout is the most common inflammatory arthritis affecting men, with high rates of early onset, severe and destructive disease in Māori and Pacific people. Joint damage frequently occurs in people with severe gout, leading to joint deformity and disability. In this laboratory study, we will examine the effects of gouty inflammation on cells in the joint that cause bone damage. We will also examine the relationship between inflammation and joint damage in people with gout. This project aims to identify new treatment approaches to treat joint damage from this disorder.
FUNDED BY: The Richardson No. 2 Trust
Ms Nikki Earle, Prof Vicky Cameron, Prof Rob Doughty, Dr Anna Pilbrow, A/Prof Malcolm Legget
Dept of Medicine, University of Auckland
Coronary artery disease is one of the leading causes of hospitalisation and death in New Zealand causing around 12,000 deaths per year, and much of this burden is avoidable through better prevention and treatment. The aim of cardiovascular risk assessments is to identify people at high risk so they can be targeted with appropriate preventative treatments, but this is not always accurate. Identifying new risk markers for the early stages of coronary artery disease before symptoms occur could improve the accuracy and allow for better targeted early intervention, for example medications or behavioural change towards healthier lifestyles. We will measure a panel of circulating biomarkers called microRNAs to see if they are associated with coronary artery disease at an early stage where plaques have built up in the arteries, but before symptoms such as chest pain or a heart attack have occurred. These will be measured in blood samples from people who have had the amount of plaque in their arteries estimated using specialised imaging techniques. Long-term, we hope these studies will also further our understanding of the mechanisms of coronary artery disease and lead to the development of new treatments.
FUNDED BY: Bruce Cole Fund
Dr Kate Faasse
Dept of Psychological Medicine, University of Auckland
Medication use in daily life occurs within a social context that is often disregarded or deliberately eliminated in randomised controlled trials. In everyday interactions, people talk with others about how effective (or not) their treatment is, and what side effects they are experiencing. Social modelling has an important influence on drug effectiveness and side effects, but it is frequently overlooked in research. In recent studies, we found that the social modelling of medication benefits can increase treatment effectiveness, and the social modelling of side effects can reduce effectiveness. Importantly, these effects were not limited to self-reported outcomes, and were seen in blood pressure and heart rate. We also found strong gender effects on the reporting of side effects. Following modelling of both medication benefits and side effects by a female model, female participants reported significantly more side effects than male participants. The proposed study will further investigate the influence of gender on the social modelling of treatment outcomes to assess how gender match or mismatch between the participant and the model influences these effects, as well as how participant empathy influences outcomes. This has broad implications for treatment outcomes in patients starting a new drug or those switching medications.
FUNDED BY: Donation from Sanford Limited
Dr Anthony Hickey, Dr Anthony Phillips, A/Prof Adam Patterson, Dr Jiwon Hong
School of Biological Sciences, University of Auckland
A range of conditions (sepsis, heavy blood loss, inflammation) can cause acute disease. Many acute disease patients die of a similar pattern of multiple organ failure (heart and lungs, then kidneys and liver). This suggests a common factor or factors, against which there are no effective treatments. We found evidence that lipid particles, which are made in the small intestine and usually distribute energy rich fats around the body, are altered in a rat model of sepsis. We propose that in acute disease, these particles carry unusual toxic components to the key organs, and promote organ failure by damaging mitochondria, the cell’s powerhouses. In this project, we will study other types of acute disease and find the common toxic components in these lipid particles that contribute to the multiple organ failure. This will provide a new method to prevent and treat multiple organ failure.
Dr Stephen Jamieson, Prof William Wilson, Prof Cristin Print, Dr Francis Hunter
Auckland Cancer Society Research Centre, University of Auckland
The genomic analysis of human tumours is developing rapidly and offers unprecedented opportunities to match anticancer drugs to individual patients. This aspect of personalised cancer medicine is already contributing to improved cancer care through the use of drugs that directly target the mutated gene products that drive cancer cell growth and through the identification of genetic biomarkers that predict patient populations most likely to benefit from targeted drug therapies. However for the most widely used anticancer agents, and for many new drugs in development, the genes that determine response to therapy are unknown. We will use a powerful new technology, called CRISPR/Cas9, to knock out essentially all genes (individually, i.e. one gene per cell) in human head and neck cancer tumour xenografts grown in immune deficient mice. This study will provide new insight into the evolution of specific clones within tumours, and will enable us to develop an experimental model that is optimised for discovery of genes that determine sensitivity to anticancer agents.
Dr Kathryn Jones, A/Prof Bronwen Connor
Dept of Pharmacology, Centre for Brain Research, University of Auckland
Parkinson’s disease (PD) is a neurological disorder resulting in severe motor deficits due to the loss of dopamine neurons in the brain. Lack of access to live, disease affected, human neurons is a barrier to understanding and treating PD. To overcome this, the proposed project will use a novel mRNA reprogramming technology to generate live human dopamine precursor cells and mature neurons from skin cells donated from patients with PD. We will use gene expression technology to examine changes between PD-derived dopamine neurons and normal dopamine neurons to better understand changes that PD-related genes cause that drive the disease. Overall, the outcomes of the project will advance our current knowledge regarding how PD genes cause dopamine cell death, and provide the basis for further research eventually leading to the establishment of early warning biomarkers and the identification of new drug targets for the treatment of this debilitating disorder.
FUNDED BY: William Douglas Goodfellow Charitable Trust
Dr Maggie Kalev-Zylinska, Prof Stefan Bohlander, Dr Lochie Teague, Dr George Chan, Dr Cherie Blenkiron
Dept of Molecular Medicine & Pathology, University of Auckland
This project will improve our understanding of blood cancers that affect megakaryocytes (platelet precursors). No specific treatments are available for patients with these disorders, and outcomes are unsatisfactory. Most frequently affected are children with Down syndrome and older people, whose tolerance of chemotherapy is particularly poor. While new therapies are needed for all patients, these two patient groups are especially vulnerable. Our work will interrogate calcium pathways in megakaryocytic cancers using modern methods. We will examine mechanisms that lead to disease development and aim to identify new therapy targets. Our results will help characterise patient cancers and guide development of novel, targeted drugs that are safer and better tolerated by patients.
Dr Julie Lim, Dr Joanna Black, Prof Paul Donaldson
Dept of Optometry & Vision Science, University of Auckland
As we age, our bodies are exposed to a greater degree of oxidative damage. In the eye, this manifests itself through the development of cataract, glaucoma and corneal opacities; eye diseases that collectively account for more than half of the blindness in the world. Previous work has revealed that the cystine-glutamate antiporter (CGAP) in the lens may play a key role in maintaining redox balance within the eye and minimising oxidative stress to surrounding tissues. To test this hypothesis, redox balance will be genetically modified in mice by deletion of the CGAP gene either in all tissues or specifically within the lens. Through biochemical and clinical assessments of these mouse models, we will determine the effects of global and local redox imbalance on oxidative stress pathways and ocular function. Collectively, our findings will aid in our understanding of redox signalling systems in the eye and validate the utility of our knockout mice as a potential model for identifying new strategies for delaying the onset of age related eye diseases and maintaining long term ocular health.
Dr Andrew McDaid, Ms Anna McRae, Dr James Stinear, A/Prof Cathy Stinear
Dept of Mechanical Engineering, University of Auckland
Over 7,000 New Zealanders suffer a stroke every year. The rehabilitation and hospitalisation costs for stroke are amongst the highest for all injuries, estimated at NZ$450 million per year. To recover control of movement, the brain of a stroke patient reorganises its connections with other parts of the body. Part of this process involves neighbouring brain cells or a healthy part of the brain ‘taking over’ from a region of the brain that was damaged by the stroke. Much of this reorganisation happens in the early (acute) stages of recovery. The highly novel hypothesis of this project is that, by constraining the paretic leg of a stroke patient in a ‘normal’ trajectory at the acute stage of recovery, a more normal gait pattern will result than when the constraint is not imposed; in effect the patient will never be allowed to learn an impaired gait pattern. Our long-term aim is to change clinical practice by demonstrating that a simple mechanical device can prevent stroke patients from developing the inefficient and unstable gait pattern that typically afflicts chronic stroke survivors. The project is therefore focused on developing a novel acute stage stroke rehabilitation device and taking it through a pilot study.
FUNDED BY: W & WAR Fraser Charitable Trust
Dr Christopher McKinlay, Prof Caroline Crowther, Emeritus Prof Elaine Rush, Dr Mike Meyer, Dist. Prof Jane Harding
Liggins Institute, University of Auckland
Gestational Diabetes (GDM), defined as glucose intolerance (high blood glucose) first appearing in pregnancy, is an increasing health problem worldwide. Not only does it affect maternal health, but it also carries risks for the baby including being born too large, birth complications and greater likelihood of diabetes and obesity in adulthood. The rate at which a baby grows in the first 6 months influences growth patterns throughout life and this period may be particularly important for babies exposed to GDM as gaining too much fat in the months after birth is another risk factor for later obesity. Recent expert international guidelines have recommended that the threshold for diagnosing GDM should be lower than is currently used in New Zealand, but this could see rates of GDM increase substantially, up to ~18%. While treating women with mild glucose intolerance may reduce the number of large babies, it is unclear if this will translate into better health outcomes overall. In this study we will investigate if treating women with mild GDM, as diagnosed under the new criteria, will optimise infant growth and feeding patterns and prevent excessive early fat accumulation. This will assist in deciding whether New Zealand should adopt the new criteria and may help to explain why babies exposed to GDM are at increased risk of diabetes themselves.
FUNDED BY: Marion Ross Memorial Fund
Dr Dorit Naot, Dr David Musson, Dr James Markworth, Dr Justin Fernandez,Prof Jillian Cornish
Dept of Medicine, University of Auckland
Each year, over 80,000 older people in New Zealand sustain a fracture, suffering acute pain and disability and in some cases long-term loss of independence. The estimated yearly cost involved is $1.15 billion. Thus, development of novel strategies for fracture prevention and the improvement of fracture healing is a major public health priority. Our study focuses on the muscle as a source of cells and factors for the improvement of bone health, as it has long been recognised that muscle loading is coupled to increases in bone mass and strength. We will study muscle and bone cell lines in an in vitro model system that enables the application of mechanical loading. We will characterise the factors secreted from muscle cells in response to loading, and study the changes these factors induce in bone cells. In addition, we will investigate the effect of bone cells on muscle cells in early developmental stages, as there is evidence suggesting young muscle cells can differentiate into bone cells and be recruited into fracture sites to support the healing process. The muscle-derived factors identified here and the understanding of muscle cell recruitment to bone will contribute to development of strategies for improving bone health.
Dr Verity Oliver, Dr Andrea Vincent, Prof Fulton Wong
Dept of Ophthalmology, University of Auckland
Inherited retinal dystrophies are collectively a leading cause of retinal blindness, affecting 1/2000 people. Progressive degeneration of the retina results from an underlying genetic error. Replacement gene therapy has been successfully used in inherited blindness, but for this to be a potential treatment option the disease-causing gene must first be identified. We have identified a NZ family with an early-onset retinal dystrophy. Using DNA sequencing technology we have located a unique disease-causing variant in the TITIN gene. We hypothesise that TITIN plays an important role in the retina and that the identified genetic variation changes normal protein function, resulting in retinal degeneration. By using zebrafish, we propose to characterise the role of TITIN in the retina. The function of TITIN will be examined by both turning off TITIN during development and introducing the TITIN DNA variant present in our NZ family (CRISPR/Cas9 genome engineering). The zebrafish retina will be imaged using diagnostic tools identical to those used in human eye clinics. Establishing zebrafish with aspects of the human disease facilitates future drug screening and gene therapy treatments for retinal dystrophies. Understanding inherited blindness can also help our knowledge of common blinding diseases, including age-related macular degeneration.
Dr Andrea Raith, Prof Paul Rouse, Prof Matthias Ehrgott, Dr Juliane Manitz, Dr John Simpson, Dr Giuseppe Sasso, Dr Andrew Macann
Dept of Engineering Science, University of Auckland
Radiotherapy treatment is used to treat cancer in about 50% of all New Zealand cases. During treatment a patient’s tumour volume is irradiated while avoiding damage to surrounding healthy tissue. Treatment plans are developed by a planner using commercial software, in an often time-consuming iterative process, which aims to achieve a range of plan quality parameters. The oncologist reviews the plan and decides to go ahead, or that re-planning is required (which may or may not lead to actual improvement of a plan). It is impossible to tell if a plan is truly optimal; plan acceptance and quality are based on experience and intuition. We propose to develop a knowledge-based benchmarking approach to assess plan quality by on-the-fly comparison of a new plan to a library consisting of previous clinically approved plans. The proposed integration of this approach in current planning systems gives planners and oncologists feedback on plan quality avoiding un-necessary iterations, thus improving the efficiency of the planning process. Patients will benefit from receiving better quality treatments. Our goal is to help treatment planners generate better treatments for patients in a more efficient planning process thus shortening the time from diagnosis to beginning of cancer treatment.
Dr Kathryn Rice, Dr Tom Gentles, Dr Tim Hornung
Dept of Paediatrics: Child & Youth Health, University of Auckland
Some children are born with one heart pump chamber instead of two. This is the most serious type of congenital heart defect. Children with this condition require a series of operations in the first years of life, the last of which is the “Fontan” operation. Unfortunately this is not a cure. People with a Fontan circulation have reduced life expectancy, ongoing medical problems, and reduced quality of life; highlighted by their reduced ability to undertake physical activity which worsens over time. There are around 1350 people living with this circulation in Australasia. A Registry has been set up between New Zealand and Australia for people with a Fontan circulation. The Registry aims to undertake research to improve their quality, and quantity of life. This project focuses on better understanding how the Fontan circulation works. We assess both the quality of life and functional capacity of people with a Fontan circulation using sophisticated MRI and heart ultrasound imaging at rest and during exercise. Achieving a greater understanding of the Fontan circulation will allow us to develop new approaches to improve heart function, reduce medical issues, with positive impact on the quality of life for people with a Fontan circulation.
A/Prof Janie Sheridan, A/Prof Malcolm Tingle, Dr David Newcombe, Dr Natalie Walker
School of Pharmacy, University of Auckland
The use of tobacco products and exposure to tobacco smoke is recognised as the leading preventable cause of death worldwide, with an estimated 15,000 people dying of tobacco-related diseases every day. There are a number of pharmacotherapies which support smoking cessation, of which varenicline is the most effective, but also the most expensive. Cytisine, a plant-based alkaloid, is a similar type of pharmacotherapy to varenicline, but is significantly cheaper, and has been shown to be more effective than placebo. However, the product has a complex dosing regimen that has no clear basis in empirical research, and research indicates that adherence to dosing may be poor potentially reducing effectiveness. A less complex regimen is therefore likely to improve smoking cessation outcomes. We therefore propose to undertake two studies to investigate the influence of dose, dosing frequency and dosing duration and the relationship with cytisine’s effect on craving for tobacco. We hypothesise that an improved dosing regimen underpinned by scientific evidence may increase the effectiveness of the drug in the wider population. The outcomes of these studies will contribute to the design of a larger community-based trial to assess whether an improved dosing regimen can increase the effectiveness of the drug.
A/Prof Srdjan Vlajkovic, Prof Peter Thorne
Dept of Physiology, University of Auckland
Hearing loss affects 10-13% of New Zealanders and this prevalence will increase with the aging population. The most common causes of acquired hearing loss in humans are aging and noise exposure. These are associated with the loss of sensory cells and auditory neurons in the cochlea of the inner ear. Prosthetic rehabilitation via hearing aids and cochlear implants cannot repair cochlear injury, hence it is essential to develop therapies that can protect the delicate structures of the inner ear and thus preserve hearing. In this proposal we will examine how the blocking of two proteins that bind together and function as a molecular switch for adenosine receptors in the cochlea can improve the survival of cochlear tissues after exposure to noise and rescue hearing. This is potentially a critical translational research for prevention and therapeutic management of acquired hearing loss.