Medicalresearch.org.nz

Media Release
21 December 2011

Auckland Medical Research Foundation Announces December Grants

AMRF Awards over $1.8million to Auckland Researchers in its Latest Grant Round
The Auckland Medical Research Foundation (AMRF) announced today $1,864,982 in funding to
medical researchers in Auckland in its December 2011 grant round.
Foundation Executive Director Kim McWilliams says, “From our beginnings, we have promoted
research of high scientific value and purpose across the full spectrum of medical science. Many of
these researchers already have and will go on to become leaders and internationally recognised in
their particular discipline or field of medicine. This round again saw applications from emerging
scientists rise to record levels, and our response has been to fund six rather than the usual four
Research Fellowships and Scholarships. ”
The grants included 9 successful research projects ($1,029,113), two Postdoctoral Fellowship
($339,049) to Dr Valerie Anderson and Dr David Musson, four Doctoral Scholarships ($482,000), 5
travel grants ($12,820) for researchers to present their research overseas, and one Sir Douglas
Robb Memorial Fund ($2000) to fund a communication and outreach initiative. Research grants
were awarded over a variety of research areas ranging from cancer, diabetes, stem cell,
rheumatoid arthritis, skin grafts, and robotic assisted physiotherapy.
Research project summaries overleaf

The AMRF is a major independent funding agency and Charitable Trust that provides contestable
funding for medical research based in the greater Auckland region. Over the past 55 years the
AMRF has distributed over $40 million in funding to a wide range of research activities - $3.3million
distributed in 2010 alone.
For further information on the current grants awarded and application forms for future grant rounds
see our website at www.medicalresearch.co.nz
ENDS
For further information please contact:
Kim McWilliams
Executive Director
Auckland Medical Research Foundation
09 923 1701
021 339 520



GRANTS AWARDED DECEMBER 2011
PROJECTS
LONG NON-CODING RNA IN BREAST CANCER – 1111011 ($139,756 – 2 years)
Dr Marjan Askarian-Amiri, Prof Bruce Baguley, Dr Cherie Blenkiron
Auckland Cancer Society Research Centre, The University of Auckland
Human and other vertebrates have about 20,000 protein-coding genes, which make up around
1.5% of the total genome. Research in recent years has discovered non-protein-coding genes
(ncRNA). Those are situated in the remaining 98.5% of human genome and playing a critical role
in cellular functions. A new paradigm is emerging in which ncRNAs play important roles in a
variety of biological processes and are emerging as important regulatory molecules in development
and disease. Two major classes of ncRNA can be distinguished by size. Small ncRNAs have
been studied for some time, while the function of large ones, which are the dominant species of
ncRNA in humans, is still in the early stages of study. We have previously identified large ncRNAs
in human breast cancer tissue and proposed it might be involved in cancer progression. In this
study we aim to investigate the function of two large ncRNAs in human breast cancer. The results
have potential not only to understand the biology of ncRNA in cancer progression but also for
development of new biomarkers for breast cancer diagnosis and as targets for novel therapeutic
approaches.

TUMOUR-INDUCED LYMPHATICS - 1111015 ($139,412 – 2 years)

Dr Jonathan Astin, Prof Kathryn Crosier, Prof Phil Crosier
Dept Molecular Medicine & Pathology, The University of Auckland

Currently, one in three New Zealanders will die of cancer. Frequently, the cause of death is due to
metastasis, where cancer cells spread from the primary tumour and invade other parts of the body.
Cancer cells are able to spread from the primary tumour by entering either the blood or, in many
cases, the lymphatic vasculature. One of the first steps in lymphatic-mediated metastasis is the
growth of lymphatic vessels towards and within the primary tumour, however many of the signalling
pathways that underlying this response remain unknown. This project aims to identify genes that
regulate tumour-induced lymphatic growth and will form an important first step in developing
therapies to prevent or limit lymphatic-mediated metastasis.

PREVENTING ATOPY WITH VITAMIN D - 1111019 ($108,291 – 2 years)
A/Prof Cameron Grant
Dept of Paediatrics: Child and Youth Health, The University of Auckland
Asthma prevalence is increasing globally. New Zealand has one of the highest asthma rates in the
world. We do not know how to prevent asthma. We know that atopic asthma is the most common,
severe and persistent form of asthma. Atopy develops early in life in response to immune
stimulation following ingestion and inhalation of antigens. Vitamin D deficiency is another global
public health issue. It is prevalent in many countries with high or increasing asthma rates. Vitamin
D deficiency is common in NZ. Both vitamin D deficiency and asthma are more common in Māori
and Pacific in comparison with New Zealand European. Vitamin D is an immune regulator. Its
mechanism of action suggests that it could play a central role in the risk of developing atopy. We
will determine if improved vitamin D status during pregnancy and infancy reduces the risk of atopy
in children. This is a cost-effective application as it will be conducted within an established trial of
vitamin D supplementation during pregnancy and infancy. If improved vitamin D status reduces
the risk of atopy we will have found a safe, inexpensive intervention to reduce atopic asthma and,
in particular, the high rate of asthma in New Zealand.

VITAMIN D STATUS IN MĀORI AND NON-MĀORI – 1111017 ($97,329 – 18 months)

Prof Ngaire Kerse, Catherine Bacon, Avinesh Pillai, Mark Bolland, Karen Hayman, Mere
Kepa, Lorna Dyall
School of Population Health, The University of Auckland
Low levels of vitamin D have been linked to diverse range of outcomes including fractures, falls,
cancer, cardiovascular disease and diabetes. Despite New Zealand’s temperate climate and
moderate latitudinal location, New Zealanders have lower than expected vitamin D levels. Levels
in Māori are also lower than in New Zealanders of European descent. However, little is known about vitamin D status in very elderly Māori compared to their non-Maori counterparts. Life and Living in Advanced Age: the Cohort Study in New Zealand (LiLACS NZ) is a multi-faceted longitudinal cohort study examining determinants of high-quality, independent living in Bay of Plenty Māori and non-Māori in their 9th decade of life. Extensive consultation and excellent relationships with tangata whenua participating in this project have provided a rare opportunity to assess a blood biomarker of vitamin D status and its prospective effect on important health outcomes in this population. The aims of the proposed research are firstly to establish whether there are differences in vitamin D status according to ethnicity in this age-group, and secondly to determine 2-year prospective outcomes associated with baseline status. This proposal is for funding of blood biochemistry and the analysis of study data to achieve these aims.
MRI OF CARTILAGE IN RA (FOLLOW-UP STUDY) - 1111018 ($135,372 – 2 YEARS)
Prof Fiona McQueen, A/Prof Nicola Dalbeth, Dr Quentin Reeves
Dept of Molecular Medicine & Pathology, The University of Auckland
MRI scanning of the joints can reveal much about the pathology of rheumatoid arthritis (RA). Our
group has pioneered research into this area, investigating the characteristics of the joint lining
(synovial membrane), tendons, bone and cartilage using MRI. In this project we are continuing our
investigations of cartilage at the wrist in 3 groups: healthy controls, those with RA of recent onset
(within 2 years at recruitment) and patients with longstanding RA. We recruited these groups
during 2008/2009 and developed a scoring system for measuring cartilage at the wrist using MRI
scanning (now published [1] and attached as Appendix 1). Analysis of these data revealed the
surprising finding that patients with early RA had identical cartilage thickness to the healthy
controls, despite evidence of joint inflammation and bone damage. This suggests that cartilage
damage may not be the direct precursor of bone damage in RA as is traditionally assumed, but
may in fact occur later. We now wish to approach these patients and controls again and recruit
them to a follow-up study, which will involve rescanning them during 2012/2013 which would be
four years later. This will provide important information about the rate of cartilage loss in RA and a
comparison with controls. We should also be able to compare the development of cartilage loss
with the progression of bone damage and joint inflammation. From that information we hope to
further understand the pathological processes at work in the rheumatoid joint.

CARRIERS FOR SKIN GRAFTS - 1111012 ($97,329 - 18 months)

A/Prof Mervyn Merrilees
Dept of Anatomy with Radiology, The University of Auckland

A major deficiency in skin substitutes for patients requiring grafts for burns and other injuries is a
lack of elastic fibres. Using our recently discovered and novel technologies for increasing the
elastic fibre content of tissues, we have produced sheets of human skin enriched in elastin. These
sheets, however, despite being mechanically stronger than skin without elastin, are relatively thin
and less than optimal for grafting and suturing. We now propose to investigate the suitability of two
suturable and biodegradable substrates for use as carriers for our elastin enriched skin sheets.
One is a commercially available and FDA-approved wound dressing product (developed in New Zealand and called endoform) made from the lamina propria of sheep stomach; the other an electrospun mesh made from bioabsorbable suture material, to be produced by Electrospinz, Blenheim. Our preferred method for stimulating elastin is over-expression of a matrix gene called V3. Given the FDA’s continuing lack of approval for gene therapy, however, we propose to enhance production of elastin in our skin sheets using recombinant V3 protein as the stimulus. The overall aim of the project is develop strategies that can be applied in the clinic in the near future, without being reliant on the uncertain regulatory environment that surrounds gene therapy.
PILVAX - 1111016 ($83,504 – 1 year)

A/Prof Thomas Proft
Dept Molecular Medicine & Pathology, The University of Auckland
Despite the previous successes in vaccine development (e.g. smallpox, polio, diphtheria, tetanus),
vaccines against a number of important diseases are still unavailable (e.g. HIV, malaria). Vaccine
development has progressed from killed or attenuated microorganisms to subunit vaccines based
on individual proteins or peptides. However, peptides by themselves are often poorly
immunogenic and require administration with potentially toxic adjuvants or amplified (multimeric)
peptides. We propose to develop a novel peptide delivery system by expressing antigens within
the group A streptococcus (GAS) pilus structure on the surface of Lactococcus lactis. This will
have several advantages, such as increased peptide stability due to the rigid pilus structure,
biocompatibility (no synthetic peptide carriers and adjuvants), and time/cost effectiveness (no
chemical coupling). We will initially focus on two peptide epitopes from the conserved region of the
M protein of GAS, a human pathogen that causes toxic shock and rheumatic fever. We will
develop mouse models to evaluate immune responses and to investigate the optimal route for
delivery of the vaccines.

MiG TOFU: 7-9 YEAR OLDS - 2111013 ($122,551 - 2 years)

Dr Janet Rowan, Prof Elaine Rush, Dr Jun Lu, Dr Malcolm Battin, A/Prof Lindsay Plank
National Women’s Health, Auckland District Health Board

Children who are born to women who have diabetes diagnosed in pregnancy (GDM) have
increased risks of obesity and diabetes as they grow up, which, in part, may relate to exposure to
increased sugar levels in the womb. Treatment of women with GDM improves pregnancy
outcomes, but it is unclear whether it improves long term risks for the children. The aim of this
project is to compare 7-9 year old children of women who had GDM and were treated with either
insulin injections or metformin tablets to help control the blood sugar level. Insulin does not cross
to the baby but metformin does, so it could influence children’s later growth and development. The
children have been compared at two years of age and the findings suggest that the children whose
mothers took metformin may store their body fat in a healthier way, which could reduce their later
risk of diabetes. This follow up is to further confirm the safety of metformin in children exposed in
the womb and to examine body fat deposition in more detail plus other risk factors for diabetes.
This study has major implications for future treatment of women with GDM.

ROBOTIC GAIT REHABILITATION SYSTEM - 1111014 ($138,753 – 2 years)

Prof Shane Xie
Dept of Mechanical Engineering, The University of Auckland

Neurological disorders such as stroke and incomplete spinal cord injuries (ISCI) often result in
lower limb disability and loss of mobility. Robot driven physiotherapy has been actively researched
in the past two decades to help physiotherapists provide better treatment. However, existing
designs of robotic gait orthoses are extremely heavy and rigid and are not suitable to work with
human users. Moreover, these orthoses forces the subject’s limbs on predefined tracks without taking into account patient’s disability level. In order to advance the present state of robotic physiotherapy, this project will investigate a new design of robotic orthosis which will be more flexible, light weight and with the use of special muscle like actuators; the actuation of the robotic orthosis will be more compliant, soft and human friendly. Besides design improvements, we will also develop an intelligent controller based on ‘assist-as-needed’ approach whereby the robotic assistance to the subjects can be attuned to their neurological impairment levels. Methods will be developed to identify subject’s musculoskeletal capabilities using robot as a tool and thereby therapeutic outcomes will be assessed. Physiotherapy, employing our new robotic orthosis design, intelligent controller and methods to identify musculoskeletal function, will be safe, objective and evidence based.
POSTDOCTORAL FELLOWSHIPS
BIOMARKERS FOR TREATMENT RESISTANT SCHIZOPHRENIA - 1311001 ($179,267 – 2
years)

Dr Valerie Anderson
Centre for Brain Research, The University of Auckland

Standard medications are not affective in approximately a third of people with schizophrenia, and
these patients are considered ‘treatment-resistant’. Alternative medication and combinations of
antipsychotics must be used, but these medications have a greater risk of inducing serious side
effects and therefore are avoided where possible. Consequently, people with treatment-resistant
schizophrenia often experience many years of unsuccessful therapy with standard medications
before alternatives are prescribed, during which time their symptoms severely affect daily living
and have a significant impact on long-term outcomes. This project aims to identify measurable
biological characteristics (biomarkers) that could be used to predict whether people with
schizophrenia will be treatment-resistant. Brain magnetic resonance imaging,
electroencephalography, and neuropsychological data will be collected and analysed to investigate
the structure and function of the brain in people with schizophrenia who are treatment-resistant,
and the findings compared to people with schizophrenia who respond well to standard medications
and normal subjects. Identification of reliable biomarkers to predict treatment-resistant
schizophrenia would enable alternative medications to be prescribed earlier in the disease course.
This will ultimately minimise the time that these patients experience debilitating symptoms, leading
to improved outcomes for them, and reducing the burden on their families and health care
providers.

EVALUATION OF SCAFFOLD MATERIALS FOR TENDON REGENERATION

Dr David Musson – 1311002 ($159,782 – 2 years)
Dept of Medicine, The University of Auckland
Tendons are specialised tissues that connect muscle to bone and transmit tensile forces from
muscles to generate joint movement. Tendon injuries are a common clinical problem thought to
affect one in every two thousand otherwise healthy, active people. Damaged tendons heal slowly
and the formation of fibrotic scar tissue at the wound site alters the biomechanical properties of the
tendon, thus re-tear rates are high. Tissue engineering has the potential to contribute to
successful tendon healing. Using this approach a biomaterial scaffold can be inserted at the site of
injury, providing temporary mechanical support, while ultimately enhancing tissue regeneration.
Possible scaffolds used in this area are human tissue grafts and extracellular matrix (ECM)
scaffolds. Human tissue grafts require no FDA approval, while ECM scaffolds merely require
premarket approval which involves no preclinical/clinical proof of efficacy. However, both are
marketed for, and often utilised in, rotator cuff surgery. Only a limited number of studies have been
published, with inconsistent surgical outcomes reported. Our aim is to develop a stringent testing
system for potential scaffolds in this area to help refine potential scaffolds for use in tendon tissue
regeneration. We have done some preliminary work in this area on commercially available scaffolds.
DOCTORAL SCOLARSHIPS

GLUTAMATE RECEPTORS IN HUMAN MELANOMA – 1211001 (116,000 – 3 years)
Miss Stacey D’mello
Dept of Molecular Medicine & Pathology, The University of Auckland
The incidence of melanoma in New Zealand is one of the highest in the world but current treatment
options remain unsatisfactory. Glutamate and its receptors have recently emerged as potential
novel therapeutic targets. However, very little is known about them in this disease. Research
studies so far demonstrated that certain glutamate receptor inhibitors suppress melanoma growth
in experimental models. There are also promising results from early clinical trials that observe
deficiency of glutamate release inhibition in patients with advanced melanoma tumours. In
addition, over 30% of melanoma patients have been found to carry mutations in a previously
unsuspected glutamate receptor gene that codes for the N-methyl-D-aspartate receptor (NMDAR).
Virtually nothing is known about NMDARs in melanoma whereas, a lot is known about them in the
brain. Knowledge from neuroscience can be used to guide the process of study of the NMDARs in
melanoma cells. Here, I propose to investigate NMDAR expression and function in the New
Zealand collection of human melanoma cell lines that are available through the Auckland Cancer
Society Research Centre (ACSRC). My project will investigate how NMDARs contribute to the
biology of melanoma. The overall aim is to determine if NMDARs can be used as novel
therapeutic targets of human melanoma cell lines that are available through the Auckland Cancer
Society Research Centre (ACSRC). My project will investigate how NMDARs contribute to the
biology of melanoma. The overall aim is to determine if NMDARs can be used as novel
therapeutic targets.

GENETIC VARIANTS AND SCD – 1211002 ($122,000 – 3 years)
Miss Nicola Earle
Cardiovascular Research Group, The University of Auckland
Sudden unexpected cardiac death is common and its effect on families and communities can be
devastating. Up to 50% of sudden unexplained deaths in people less than 40 years old are due to
inherited heart diseases such as long QT syndrome and Brugada syndrome. These syndromes
are caused by variants in the genes that help regulate cardiac cells and consequently the heart
rhythm. Many of these deaths can be prevented by identifying and treating high-risk individuals in
the community, and although diagnostic genetic testing is already a vital part of this, there is
interest in increasing its sensitivity. While in older people cardiac arrest is often a result of
acquired conditions such as coronary artery disease, an individual’s risk is in part due to genetics.
Further research is needed on early predictors for these events, and genetic markers will play a
key role. By analysing large numbers of samples from New Zealand, Australia and the US and
using established and novel techniques, this project will examine both common and rare genetic
variation and the related risk of sudden cardiac death. Further information on the genetic basis of
these diseases will allow improved screening and ultimately reduce the number of deaths.

PRETERM STEM CELL THERAPY – 1211003 ($122,000 – 3 years)
Miss Lotte van den Heuij
Dept of Physiology, The University of Auckland
In New Zealand alone, approximately 500 babies are born prematurely per year. Approximately
50% survive with significant neurological and cognitive disability and approximately 10-15%
develop cerebral palsy. This neuro-developmental disability is devastating for families and poses a considerable challenge to the finite education and health care resources of New Zealand. Currently there is no effective treatment to prevent or reduce damage or to help the brain repair itself after injury has occurred. Neuro-developmental handicap is due to brain damage that occurs after insults such as oxygen deprivation. Recent research in adults suggests that stem cells derived from amniotic membranes that are normally discarded at birth may help protect and repair the brain after oxygen deprivation. This potential for benefit may be even greater in the immature brain since as it has a greater capacity for producing new brain cells. Also in the immature brain stem cells migrate more extensively and commonly differentiate into brain cells typically lost following oxygen deprivation. In the current project, we will undertake the first preclinical studies using an experimental model of fetal brain injury to test the therapeutic usefulness of these stem cells.
VISUAL BRAIN PLASTICITY IN ADULT HUMANS – 1211004 ($122,000 – 3 years)

Mr Victor Borges
Dept of Optometry & Vision Science, The University of Auckland
One of the most exciting areas of research into the human brain is trying to understand the brain’s
capacity to reorganise itself following injury, a process known as plasticity. Functional magnetic
resonance imaging (fMRI) is a non-invasive technique, which allows for recordings of the brain’s
activity to be made while people are performing different tasks. Using this powerful tool, I will
evaluate the structural and functional changes that occur to the visual areas of the brain following
injury to the optic nerve, which propagates information from the eye to the brain. This project will
focus on the changes caused by acute stroke to the optic nerve and the neurodegenerative
disease glaucoma which affects the cells of the optic nerve. This study will increase our
understanding of the human brain’s ability to reorganise following injury and consequently inform
new and innovative treatment modalities.

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