Awarded Project grants

Awarded Project Grants 2018

  • 26 Jun 2018

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June Round

Immunooncology of Merkel Cell Carcinomas ($25,000 – 6 Months) 1118005

Dr Cherie Blenkiron, Dr Kate Parker
Department of Molecular Medicine & Pathology, The University of Auckland

Merkel Cell Carcinoma (MCC) are a rare tumour that are often identified as small red, quickly growing lumps on the skin. As well as growing quickly they can also spread or metastasise to other sites in the body. MCCs are caused either by an infectious virus or more often here in New Zealand by genetic damage caused by sun exposure. These two environmental triggers themselves can be the downfall for the tumour, causing an immune response or white blood cell attack. The tumour can however overcome this attack through molecular camouflage. This is where new immunotherapies, like the Melanoma treatment Keytruda can be used to reawaken the immune cells. In order to understand whether people with MCC could benefit from immunotherapy, this study will identify the types of immune cells present in these tumours and decipher their molecular camouflage signals. The project will provide new biological information about an understudied rare cancer and in the long term it could support the provision of funded immunotherapy for people with MCC.

Whānau experience of a healthy homes initiative ($14,259 – 1 year) 1118001

Dr Kyle Eggleton
Department of General Practice & Primary Health Care, The University of Auckland

Cold damp houses are associated with poorer health outcomes. Significant evidence exists demonstrating that housing insulation may reduce exacerbations of asthma and respiratory illnesses. There are a number of healthy homes initiatives nationwide and this research intends to explore one such initiative, based in Northland, to ascertain whānau experiences of the programme. The research will determine the wider health benefits of insulating and warming damp homes and whether the implementation of the project has met whānau expectations. The intent of the research is to improve the delivery of healthy homes initiatives in order to align with whānau expectations.

CGRP and bone healing ($160,000 – 2 years) 1118008

Dr Brya Matthews, Dr Christopher Walker, Dr Dorit Naot
Department of Molecular Medicine & Pathology, The University of Auckland

Bone fractures cause severe morbidity in both young, active people, and in the elderly. Fracture healing is significantly delayed or fails to occur in approximately 10% of patients. Limited treatment options are available to treat poor fracture healing, so more insight is needed into the mechanisms involved in the healing process. Sensory nerves are abundant in bone tissue, more so following injury, however their function in the healing process is not understood. One of the neurotransmitters produced by these nerves is known as CGRP and has previously been shown to promote bone formation. We will try to understand the role of CGRP in bone healing using a mouse model that lacks CGRP, as well as performing cellular studies to understand the mechanisms by which CGRP promotes bone cell activity.

Characterising the role of cardiac neurons in heart rhythm ($154,539 – 1.5 years) 1118003

Associate Professor Johanna Montgomery, Dr Jesse Ashton, Dr Kirsten Finucane, Dr Martin Stiles, Professor Bruce Smaill, Professor Julian Paton
Department of Physiology, The University of Auckland

Abnormal heart rhythms, termed arrhythmias, are devastating disorders. The most common arrhythmia, atrial fibrillation (AF), significantly increases the risk of stroke, heart failure, and dementia. Treatment strategies are limited, and more precise therapies are essential. One treatment target is the neurons located on the heart. These neurons regulate heart rhythm, and they can trigger AF. However, how these neurons trigger AF is unknown, which limits our ability to precisely target them to increase treatment success. We have assembled a team of scientists and clinicians with expertise in neurophysiology, cardiac physiology, cardiology and cardiac surgery. This enables us to examine the properties of cardiac neurons in animal models and human tissue for the first time. We hypothesise that changes occur in these neurons, termed “plasticity”, driving abnormal neuron activity in AF. We will identify the changes in cardiac neuron function during normal heart rhythm versus AF, and whether these changes can be reversed to stop AF. We will also establish protocols to precisely record from human cardiac neurons collected during heart surgery. Our novel data sets will advance our understanding of cardiac neuron function during normal and abnormal heart rhythm, which is critical to develop more precise therapies to treat AF.

Benzenesulphonamides: A promising new class of immunosuppressants ($158,808 – 2 years) 1118004

Dr Julie Spicer, Dr Kate Gartlan, Dr Stephen Jamieson, Professor Geoff Hill
Auckland Cancer Society Research Centre, The University of Auckland

Stem cell transplantation is used to treat cancers such as leukaemia, lymphoma and myeloma, but in many cases the patient’s immune system sees the incoming cells as ‘foreign’ and they are rejected, often with fatal consequences. This is because without a perfectly-matched donor, the procedure relies on mis-matched grafts from stored umbilical cord blood or partly-matched grafts from relatives. The cells responsible for early rejection overwhelmingly use a protein called perforin to kill the transferred stem cells. We have developed a class of small molecules that can block this process in the critical period of 4-5 days after the transplant. This will allow far more stem cells to survive and migrate to the marrow where they will essentially be in a ‘safe haven’ and able to multiply to produce red blood cells, white blood cells and platelets. Effective perforin inhibitors would increase the number of successful stem cell transplants, improving survival from potentially fatal cancers and with applications in solid organ transplantation more generally. In this project we plan to optimise the potency, physicochemical and pharmacological characteristics of these molecules to give safe and efficacious candidates suitable for pre-clinical development.

Inflammation and Cochlear Implantation ($158,942 – 2 years) 1118002

Professor Peter Thorne, Associate Professor Phil Bird, Associate Professor Srdjan Vlajkovic, Dr Andrew Wise, Dr Ravindra Telang
Department of Physiology, The University of Auckland

Deafness is a leading cause of disability worldwide and affects over 18% of New Zealanders. It occurs predominately from injury or disease of the cochlea of the inner ear and the primary treatment is with hearing aids or cochlear implants. Cochlear implants, normally for people with total deafness, are now available for people with some residual hearing but in many cases the hearing can deteriorate following implantation, possibly due to inflammation from surgery. This research will investigate a novel approach to reduce the inflammation by applying an activator (or agonist) of the Adenosine receptors in the cochlea that have been shown to inhibit inflammation in other tissues. We will test this in an animal model by applying the drugs loaded into nanoparticles, which are inserted surgically along with the implant. Our preliminary findings show that these drugs can reduce the post-implant deterioration in hearing and in this study, we will confirm if this is due to inhibition of inflammation. If these studies are successful, it should be easily translatable to treating patients during implant surgery as the compounds are already approved for use in humans. Protecting the ear during surgery is important to maximise the outcome of the cochlear implant.

The role of Epac in diabetic heart disease ($155,688 – 2 years) 1118006

Dr Marie-Louise Ward, Dr Sarbjot Kaur, Mr Nicholas Kang, Professor Peter Ruygrok
Department of Physiology, The University of Auckland

Type 2 diabetes (T2D) is one of the largest and fastest growing health issues within New Zealand, and is closely linked with the development and progression of cardiovascular diseases, including cardiac dysfunction, arrhythmias and heart failure. Decades of research using experimental animal models of diabetes suggest that the development of diabetic heart disease is progressive, beginning soon after the onset of diabetes, and resulting in subcellular changes to the cardiomyocytes that impact upon their function. Recently, exchange proteins activated by cAMP (known as “Epac”) have been shown to induce alterations in intracellular calcium regulation when activated in many cell types, including heart muscle. Cyclical changes in intracellular calcium control contraction and relaxation of heart muscle, which enables it to function as a pump. Experimental activation of Epac in isolated heart cells upsets calcium cycling. This results in less calcium available for excitation-contraction coupling, and an increased susceptibility to developing arrhythmias. Incomplete relaxation between beats can also occur if calcium within the muscle cells remains high. Our study will investigate Epac in tiny human atrial tissue samples obtained from consenting patients undergoing routine surgery. We hypothesise that altered Epac activation and location in T2D promotes abnormal muscle cell calcium handling. We aim to test this by measuring the relative abundance and distribution of the Epac isoforms (1 & 2), as well as their function and ultrastructural organization in atrial tissue samples from non-diabetic and T2D patients. This study will provide new knowledge of human T2D and the cellular changes that are detrimental to the heart during diabetes.

Novel treatment for acute pancreatitis ($159,266 – 2 years) 1118007

Professor John Windsor, Dr Jiwon Hong
Department of Surgery, The University of Auckland

Acute pancreatitis is a common and potentially fatal disease for which there is no specific drug treatment. Our studies have provided a new treatment paradigm that is based on the concept that the gut becomes leaky during acute pancreatitis and that toxic factors are taken up by gut lymph and drained into the main blood circulation. These toxic factors cause severe inflammation and injury to vital organs such as the heart, lungs and kidneys, which in turn results in a worse clinical outcome. This project is the first to test two types of drugs which specifically target key factors in the gut-lymph responsible for it’s toxicity in acute pancreatitis. The first study is designed to show that these two drugs are taken up preferentially by gut lymph and as a result reduces the toxicity of the gut-lymph when tested on cultured cells. The second study is designed to show that one of the drugs is effecting in reducing inflammation and organ injury. These critical proof-of-principle studies will directly contribute to further drug development and to the design of larger clinical studies which are necessary to translate this new treatment strategy for acute pancreatitis.

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December Round

Novel peptide antibiotics targeting antimicrobial resistance ($159,824 – 2 years) 1118013

Dr Ghader Bashiri, Dr Paul Harris, Dr Stephen Ritchie
School of Biological Sciences, The University of Auckland

Antimicrobial resistance (AMR) is a pressing global health issue of the modern age. In February 2017, the World Health Organisation published a list of antibiotic-resistant “priority pathogens” that pose an imminent threat to human health. These include both methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA), which are major causes of hospital-acquired and community infections. We have recently discovered a novel antibiotic with potent activity against these antibiotic-resistant bacteria, however, the antibiotic is complicated to make synthetically and can only be extracted in minute amounts from the natural source. This multidisciplinary project will use a powerful combination of chemical peptide synthesis and recombinant enzyme engineering to yield sufficient quantities of this new antibiotic for clinical application. The expected outcomes of this research address a key National Science Challenge to reduce the burden of major health problems in New Zealand, but its impact will be far-reaching as new-generation antibiotics are urgently required worldwide.

Incidence study of SUDEP in New Zealand ($75,367 – 2 years) 2118014

Dr Peter Bergin, Professor Jonathan Skinner, Dr Yannan Jiang, Dr Claire Spooner, Dr Simon Stables, Dr Elizabeth Walker, Dr Nicholas Child, Dr Ian Rosemergy, Associate Professor Roderick Duncan, Dr Melinda Nolan
Neurology, Auckland District Health Board

Sudden unexpected death in people with epilepsy (SUDEP) is an under-appreciated tragedy. It has devastating effects on families, friends and colleagues of those who die. The incidence of SUDEP is not well known, and it has not previously been studied in New Zealand; however, the life-time risk of SUDEP for someone who develops epilepsy before age 1 and who continues having regular seizures may be as high as 8%. We will undertake a prospective study to identify all people who die from SUDEP in New Zealand. We intend to identify patients from multiple sources: doctors, coroners, pathologists, Epilepsy New Zealand field workers, the epilepsy community generally, and the Ministry of Health national administrative datasets. All cases of possible SUDEP will be reviewed by two adult or paediatric neurologists and at least one pathologist, and cases will also be discussed at a meeting of the Cardiac Inherited Diseases Group. Patients in whom no clear cause of death is identified will have a ‘molecular autopsy’ in which known genes associated with sudden death are assessed. Patients who are deemed to have died from SUDEP will have information about their epilepsy and the circumstances of their deaths entered into the EpiNet database. We will calculate the incidence of SUDEP in New Zealand and determine which people with epilepsy are at greatest risk of dying. We will monitor the incidence over time to see if changes in epilepsy management result in a change in SUDEP incidence.

Household transmission of bacterial resistance ($145,078 – 2 years) 1118020

Associate Professor Catherine Byrnes, Dr Emma Best, Dr Rachel Webb, Dr Adrian Trenholme, Dr Susan Morpeth, Dr Catherine Bremner, Dr Hamish McCay
Dept of Paediatrics, Starship Children’s Hospital, Auckland District Health Board

The increased prevalence of antibiotic-resistant bacteria in New Zealand is concerning. It is driven by high antibiotic use. Worldwide infection by untreatable bacteria is projected to cause more deaths than cancer by 2025. Recently prolonged oral azithromycin (an antibiotic and anti-inflammatory medication) resulted in reduction of infections and hospitalizations for children with the lung scarring ‘bronchiectasis’. This is a group with few other available treatments leading to PHARMAC recently funding oral azithromycin for children with bronchiectasis and frequent infections for up to 12 months. As this policy is taken up, we will investigate the development of antibiotic resistance in bacteria carried by these children. However, more importantly we will also determine if the resistant bacteria are transmitted to otherwise healthy siblings in the household. Regular nose and throat swabs taken at the beginning, during and after azithromycin treatment will be cultured for bacteria and resistance patterns identified. If we show there is spread of resistant bacteria, this could significantly impact the wider community by reducing future antibiotic treatment options for others. We will also describe any factors that could improve treatment to the individual but prevent acquisition of resistant-bacteria to other household contacts.

Inosine for Bone Health ($160,000 – 2 years) 1118012

Professor Nicola Dalbeth, Distinguished Professor Ian Reid
Dept. of Medicine, The University of Auckland

Recent observational studies have reported that high urate levels are protective in the development of thin bones (osteoporosis) and fractures. Inosine is a nutritional supplement that increases serum urate levels. We plan a six month randomised controlled trial of 120 postmenopausal female participants. Participants will be randomised to one of two groups: placebo or inosine tablets. We will study markers to bone health to understand whether this supplement has effects on bone. We will also study whether this supplement can be used safely in this study population, by monitoring measures of kidney function, blood pressure and other features of metabolic syndrome. If inosine does have positive effects on bone markers, this supplement may represent a new treatment strategy for prevention of osteoporosis.

Cross talk between tissues of the eye ($158,981 – 2 years) 1118009

Dr Julie Lim, Professor Paul Donaldson, Associate Professor Dipika Patel, Dr Angus Grey, Associate Professor Philip Polkinghorne, Dr Rasha Altaie
Dept. of Physiology, The University of Auckland

With an aging population, age related pathologies of the eye are increasingly common resulting in the need for surgery. However, clinical evidence suggests that in two of the most commonly performed eye surgeries, cataract surgery and vitrectomy, the risk of secondary eye diseases is significantly increased resulting in patients requiring treatment within 2 years post-surgery. To investigate the molecular mechanisms that contribute to these secondary pathologies, we propose a novel hypothesis in which the lens and vitreous humor work together to maintain high concentrations of antioxidants in the vitreous humor. These antioxidants consume oxygen to ensure low oxygen levels which is required to protect the lens from cataract and the vitreous humor from degeneration. If this hypothesis is correct, a major impact of this project is the development of new post-cataract or vitrectomy treatments to enhance antioxidant levels in the eye and improve vision outcomes for the elderly.

Does CYREN determine radiation-induced tumour mutational burden? ($156,091 – 2 years) 1118016

Dr Barbara Lipert, Professor William Wilson, Dr Francis Hunter, Professor Cristin Print
Auckland Cancer Society Research Centre, The University of Auckland

Targeted antibodies (immunotherapy) that harness the body’s natural defence mechanisms have changed the paradigm of oncology. As one example, immunotherapy with T cell checkpoint inhibitors has shown success in shrinking even advanced tumours. Yet, at present these drugs help only a minority of patients predominantly due to the ability of cancer cells to make themselves invisible to the immune system (so-called ‘cold’ tumours). Radiotherapy can induce DNA mutations leading to formation of altered proteins (neoantigens), which can target tumour cells for elimination. Several studies have shown that high levels of mutation increase the number of neoantigens and that combining radio- and immunotherapy improves tumour control, including for patients failing radiotherapy alone. However, there are no methods for identifying patients who may benefit from this novel approach. CYREN is a small protein that we have recently discovered to be a suppressor of radiation-induced mutations. We will test whether CYREN influences mutational burden in cancers of the head and neck, and whether its inhibition enhances the antitumour activity of radiotherapy in combination with T cell checkpoint immunotherapy. If confirmed, this would help identify patients who would benefit from this treatment and would open the way for CYREN inhibition for enhancing cancer therapy.

Synbiotics and liver transplantation ($123,943 – 2 years) 1118011

Associate Professor Lindsay Plank, Associate Professor Mike Taylor, Professor John McCall, Professor Edward Gane, Dr Adam Bartlett
Dept. of Surgery, The University of Auckland

Liver transplantation is the only effective treatment for patients with advanced liver disease. This is a major operation which is associated with a high rate of complications over the early postoperative period which prolongs stay in hospital and is a major cause of early death. These complications are predominantly bacterial infections. A combination of prebiotics and probiotics (synbiotics) provided for one day before and 14 days after transplant has been shown to almost eliminate bacterial infections. This remarkable result requires confirmation for this treatment to be accepted into routine clinical practice. We propose to conduct a similar study using the same synbiotic. If this simple and inexpensive treatment reduces infections after transplant we expect it to lead to routine use in our liver transplant unit and adoption by other centres worldwide. This result and the associated reductions in antibiotic use and length of hospital stay are significant both for patients undergoing this life-saving procedure and for the hospital, given the consequential cost savings. We will also examine potential mechanisms that might explain the purported benefits of this treatment

NeuTin ARI ($104,556 – 2 years) 1118018

Dr Grant Searchfield, Professor Nikola Kasabov
Section of Audiology, The University of Auckland

Tinnitus is the perception of sound in the absence of an external physical sound source. It is a highly prevalent condition affecting 6% of the New Zealand general population and 13.5% of over 65’s. Tinnitus disrupts: hearing, attention, sleep, and can lead to anxiety and depression. There is no cure for tinnitus. However a short loud sound can partially, and in many cases totally, suppress tinnitus for a brief time. This effect has been labelled Acoustic Residual Inhibition (ARI) and is the focus of the proposed research. This research will investigate the behavioural effects and neural correlates of ARI. It will use Electroencephalography (EEG, “brain waves”) and a computer model of neurons developed in NZ called the NeuCube to understand the processes responsible for tinnitus generation and its suppression. Knowledge of the neuronal responses to tinnitus suppression will lead to the further development of novel sound therapy paradigms, and potentially targets for tinnitus medicines. This innovative research builds on previous successful AMRF funded research.

MRI study of placental oxygenation in pregnancy ($24,600 – 1 year) 1118010

Professor Peter Stone, Dr Alys Clark, Dr Seyed Ali Mirjalili
Dept. of Obstetrics & Gynaecology, The University of Auckland

Late stillbirth in normally formed babies is responsible for a majority of perinatal deaths. We were the first to show that maternal sleep position may be a major modifiable risk factor for late stillbirth, but exactly how and why position impacts on fetal well-being remains to be determined. Using MRI we showed that the supine position in late pregnancy caused a 15% reduction in cardiac output and a 36% reduction in blood flow in the lower aorta. This project aims to determine if these changes in blood flow cause reduced oxygen delivery to the baby. We have developed an international collaboration to use novel techniques to measure blood flow in the arteries supplying the womb and to measure both the maternal and fetal oxygen signals recorded by MRI. We plan to study healthy pregnancies first but in the future we would plan to apply our new knowledge to women at particular risk of stillbirth such as when the baby is not growing as expected or when the mother notices reduced movements of the baby.

Identifying impaired infant muscle growth ($154,878 – 2 years) 1118015

Professor Susan Stott, Associate Professor Malcolm Battin, Dr Seyed Ali Mirjalili, Dr Justin Fernandez, Dr Sian Williams, Dr Geoffrey Handsfield, Associate Professor Alicia Spittle
Dept. of Surgery, The University of Auckland

The first years of a child’s life are fundamentally important in shaping the child’s future health, growth and development. During infancy, extraordinarily rapid muscle growth occurs as both the brain and movement develops. Unfortunately not all children will develop at the same rate or to the same extent. For a baby born prematurely, we know that in many cases there may be lifelong effects on neurodevelopmental functioning, including impaired movement development and risk of cerebral palsy. Surprisingly, there is little research documenting typical muscle growth in infants, and how the muscle growth changes once infants begin to reach motor-milestones. Even less is known of muscle development in premature babies, who may be at risk of cerebral palsy, a condition in which children are known to have substantially smaller and weaker muscles already by the age of 2 years. Understanding typical muscle growth through this important period of development has the potential to help us identify ‘at risk’ infants and plan earlier intervention for those struggling to achieve these key motor-milestones.

Medication use in breast cancer patients ($159,253 – 2 years) 1118017

Dr Sandar Tin Tin, Professor Diana Sarfati, Professor Ross Lawrenson, Professor Mark Elwood, Associate Professor Ian Campbell, Professor Bruce Arroll, Associate Professor Vernon Harvey
Section of Epidemiology & Biostatistics, The University of Auckland

Cancer patients are commonly burdened with comorbidities and often use multiple medications. This may have an impact on cancer treatments and outcomes. This research aims to investigate the use of prescription medications for non-cancer related indications in women with primary invasive breast cancer. The data consolidated from four regional breast cancer registers will be used, which covers about 63% of all breast cancer registrations in New Zealand. Patient data will be linked to pharmaceutical, hospital discharge and mortality data. The findings will provide insight into medication use and related consequences in breast cancer patients in New Zealand, and will inform policy, practice and efforts to improve cancer care and outcomes and reduce inequities.

Exosome-Liposome Hybrids for Tumour Targeted Drug Delivery ($160,000 – 2 years) 1118019

Associate Professor Zimei Wu, Dr Euphemia Leung, Professor Larry Chamley
School of Pharmacy, The University of Auckland

Nano-sized liposomes are perceived as ‘magic bullets’ for tumour-targeting and have been successful in clinical translation. However, challenges remain including their poor tumour tissue penetration and slow release of drugs once in cells. Recently, exosomes (30-100 nm), vesicles secreted from cells, have emerged as attractive drug carriers. As natural transporters, exosomes play a major role in cell-to-cell communication, and have the ability to travel to remote locations and penetrate tissues. In this proposal, we aim to engineer a liposome-exosome hybrid, combining the beneficial features of exosomes and liposomes for targeted intracellular drug delivery to cancer cells, while sparing healthy cells. Macrophage-derived exosomes will be utilised to engineer hybrids by fusion with pH-sensitive liposomes (PSL). Unlike conventional liposomes such as Doxil® (liposomal doxorubicin), PSL rapidly release their payload into cells. This will be paired with a tumour-targeting ligand to promoting specific uptake of the hybrids by cancer cells. We will then test the doxorubicin-loaded hybrids for augmented cell- and tumour- tissue penetration capabilities. Utilising the applicants’ research strengths in different fields, this cutting-edge collaborative research proposal has the potential to revolutionise strategies for tumour-targeted drug delivery.

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