The Council of the Otago Medical Research Foundation invites applications for grants to support medical research in the Otago area relating to human health or the basic sciences of relevance to medicine.
Funds (normally <$35,000 and for one year only) will be made available for working expenses, including small items of equipment, and salaries (fixed term) of research workers. Applications solely for equipment will not be considered.
Annual Grants 2017
OTAGO MEDICAL RESEARCH FOUNDATION ANNUAL GRANTS
Sponsored by Foodstuffs Community Trust (South Island)
Associate Professor Grant Butt, Department of Physiology, School of Biomedical Sciences, University of Otago
Title of Project: Modulation of colonic epithelial proliferation and differentiation by commensal bacteria – AG342; Awarded June 2015; Project commenced August 2015.
The intestinal epithelium creates a physical barrier between the luminal contents and the body and disruption of this barrier is associated with inflammatory bowel diseases, such as Crohn’s disease (CD). This barrier consists of the mucus lining the epithelium, the different epithelial cells present in the epithelium and the rapid turnover of the epithelium. In this study, we have used human colonic organoids grown from healthy individuals and CD patients to investigate how the commensal bacteria modulate the development of the intestinal barrier through activation of toll like receptors (TLR) and how this is modified in CD. The organoids, expressed TLRs 1, 2, 4, 5 & 6 at levels comparable to that in the native colon and stimulation of TLR 2, 4, & 5 resulted in reduced proliferation. However, only TLR 4 stimulation affected the differentiation of the epithelial cells. Exposure to lipopolysaccharide (LPS) resulted in an increased expression of goblet cells in the colonic epithelium and this was associated with modulation of the Notch pathway, which determines cell lineage development in the colonic epithelium. Significantly, LPS failed to induce goblet cell differentiation in CD patients. The effect of LPS on the development of goblet cells is consistent with the observation that commensal bacteria in the intestine are important for maintenance and development of the epithelial barrier. Furthermore, the absence of this response in the Crohn’s disease tissues may contribute to the compromised barrier that is seen in these patients, which is thought to be involved in development of inflammation in Crohn’s disease.
Sponsored by JN Lemon Trust
Associate Prof Merilyn Hibma, Dr Heather Cunliffe, Department of Pathology, Dunedin School of Medicine, University of Otago, and Dr Lyn Wise, Department of Microbiology & Immunology, School of Biomedical Sciences, University of Otago
Title of Project: Understanding regulation of wound closure by skin Langerhans cells – AG343, Awarded June 2015; Project commenced October 2015.
Chronic wounds are a major cause of morbidity in New Zealand, especially in those over 60. Understanding wound closure is a critical step towards improving healing. We have identified a suppressive role for a cell type not previously considered to be important during wound healing, the Langerhans cell. This study investigates the mechanism by which Langerhans cells regulate skin repair using our well-established wound healing model, and an innovative Langerhans cell-depletable transgenic mouse. A preliminary analysis of our RNAseq data shows 59 genes that are downregulated more than 1.5 fold in both day 6 and 9 Langerhans cell depleted mice, and 95 genes that are upregulated more than 1.5 fold. An analysis of wound tissue shows higher numbers of micro-vessels, which aid in angiogenesis, in tissues depleted of Langerhans cells. We anticipate that the knowledge gained from this research will form the foundation for therapies that regulate Langerhans cells to enhance wound repair, which will have broad application for the treatment of unresolved wounds.
Sponsored by Zonta Club of Metropolitan Dunedin
Dr Rajesh Katare, Department of Physiology, School of Biomedical Sciences, University of Otago
Title of Project: Cardiac specific restoration of Pim-1 kinase to prevent cardiomyopathy in female diabetics – AG344; Awarded June 2015; Project commenced September 2015.
Cardiac complications associated with diabetes are prevalent in women. In this study, we identified a novel micro molecule, which is specifically expressed in heart tissue and is abnormally elevated in female diabetics. We confirmed this in heart tissue samples collected from both human and mice. Importantly, these changes occur much earlier in the female diabetic heart. Therapeutically knocking down these molecules, both in the cells that are grown in culture dish and in the whole mice heart, markedly prevented the development of cardiac complications in the diabetic heart. While we expected to see a better improvement in the female heart, interestingly there was no difference between male and female hearts with regard to the beneficial effects. These results therefore identified a novel mechanistic therapeutic approach to prevent/treat heart disease in individuals with diabetes.
OTAGO COMMUNITY TRUST GRANTS
Professor Wickliffe Abraham and Dr Owen Jones, Department of Psychology, University of Otago
Title of Project: Synaptic homeostatic mechanisms in vivo – CT345; Awarded June 2015; Project commenced October 2015.
Memories are stored by changes in the strength of communication at the synaptic connections between nerve cells, i.e. by “synaptic plasticity”. We tested whether such plasticity was subject to control by the history of prior activity in the neural circuit, using awake, freely moving rats. Plasticity in the memory structure called the hippocampus was not regulated by prior activity in a connected brain region, the medial septal nucleus. But activation of adenosine receptors on astrocytes gave signs of inhibiting subsequent plasticity generation. These findings extend and support our previous culture results that non-neural cells such as astrocytes can play a key role in controlling memory storage at neuronal synapses.
Dr Heather Cunliffe, Department of Pathology, Dunedin School of Medicine, University of Otago
Title of Project: Targeting the androgen receptor in triple negative breast cancer – CT346; Awarded June 2015; Project commenced October 2015.
Triple negative breast cancer (TNBC) is an aggressive form of the disease diagnosed in 10- 25% of women with invasive breast cancer. There are currently no established options for systemic therapy for patients with TNBC other than chemotherapy. This study builds on our previously published finding that 23% of TNBC tumours express the androgen receptor (AR) a proportion of which are likely fuelled by circulating androgens. The goal of this study was to define the mechanism(s) by which AR promotes tumour progression in AR-positive TNBC. We first sought to define a series of biomarkers that defined TNBC tumours that displayed a ‘luminal’-like profile, as it has been proposed these tumours express the highest levels of AR and likely be more sensitive to AR blocking agents. Using both bioinformatics and immunological approaches, we were successful in defining TNBC tumour subtypes that are luminal-like, basal-like, and mesenchymal-like. Upon analysis of AR expression across these subtypes, we observed consistently low expression of AR in basal-like tumours and moderate to high levels of AR in both the luminal-like and mesenchymal-like tumours. This pattern was consistent across a panel of 12 TNBC cell lines representative of these same three subtypes. Our observations of AR protein expression suggest that AR positive luminal-like TNBC cases cannot necessarily be inferred as likely more sensitive to anti-androgen therapy. We next determined the sensitivity of AR positive TNBC cell lines to the AR blocking agents bicalutamide and enzalutamide (both in clinical trials for TNBC patients with advanced disease). Using next generation transcriptome profiling we currently are working to analyse and validate malignant cell signalling mechanisms consistently operational in the anti- androgen resistant cases following AR blockade. Candidate vulnerabilities have been identified in the enzalutamide-sensitive and -resistant subgroups, and combination drug treatments to target the remaining candidate ‘default’ survival and growth pathway(s) are now under investigation. This study has revealed important complexity of the role of AR signalling in TNBC that warrants further investigation to enable effective stratification of patients with AR positive TNBC to receive an AR targeted agent.
Dr Regis Lamberts, Department of Physiology, School of Biomedical Sciences, University of Otago, and Dr Chris Baldi, Department of Medicine, Dunedin School of Medicine, University of Otago
Title of Project: Unravelling the secrets of the beta-adrenoceptors in the human diabetic heart – CT347; Awarded June 2015; Project commenced October 2015.
Traditional treatment of diabetic patients with b-adrenoceptor (AR) blockers for cardiovascular disease is of benefit, however to a lesser extent than to non-diabetic patients. Dysfunction of b-AR regulation of the heart is an undervalued cause of cardiovascular complications in diabetes, and its pathology is poorly understood. We aimed to determine the expression of b-AR subtypes and their downstream proteins in human heart samples. We found that the expression of the b2-AR subtype, linked to cellular metabolic processes, was increased in patients with diabetes. However, the expression of the most common “classical” b1-AR subtype was not changed. Thus, we established an important first step to unravel the differences in expression levels of b-AR subtypes and their downstream proteins in the human heart. Thereby this OMRF/Otago Community Trust grant-in-aid has provided the essential support to obtain clinical relevant novel information on the underlying changes that occur in b-AR dysfunction of the human diabetic heart. This information is useful to design near-future biomedical research, and also to design suitable clinical research studies in diabetic patients (e.g. beta blocker comparison, carvedilol vs. metoprolol).
Annual Grants 2016
OTAGO MEDICAL RESEARCH FOUNDATION
Zonta Club of Metropolitan Dunedin (Women’s Health)
Targeting triple-negative breast cancer stem cells with the oncolytic Seneca Valley virus
Dr Mihnea Bostina & Dr Laura Burga (Department of Microbiology & Immunology), Professor Rhonda Rosengren (Department of Pharmacology & Toxicology)
Triple negative breast cancer (TNBC) is considered the most aggressive subtype of breast cancer. Currently, there is scientific consensus that targeting cancer stem cells in TNBC would reduce multi-drug resistance, malignancy, and the relapse of disease. Tumour endothelial marker TEM8 has recently emerged as a promising stem cell marker in TNBC. We have identified TEM8 as the target for Seneca Valley Virus (SVV). This virus is being examined in several clinical trials because of its ability to infect and kill cancer cells. These types of viruses also have an ability to spread and destroy the remaining tumour. This project intends to confirm the presence of TEM8 as a cancer stem cell marker by screening a large panel of TNBC cell lines and then to evaluate the cancer killing potential of SVV.
JN Lemon Charitable Trust
High-resolution imaging of host cell exocytosis during infection by the bacterium Listeria
Associate Professor Keith Ireton & Dr Mihnea Bostina (Department of Microbiology & Immunology)
Listeria monocytogenes is a food-borne bacterium that causes abortion or meningitis. In NZ and many other developed nations, Listeria infections result in high rates of hospitalization (-90%) and mortality (-20%). Critical for disease is the ability of Listeria to penetrate inside and replicate within human cells. How Listeria provokes human cells into ‘swallowing up’ bacteria is not understood. In this proposal, we use high resolution imaging approaches to test the novel idea that Listeria subverts a normal host process called ‘exocytosis’ in order to gain entry into human cells.
OceanaGold & Collective Donation for Cancer
Targeting cancer using modified T cells recognising a tumour coagulation factor
Associate Professor Alexander McLellan & Dr Sarah Saunderson (Department of Microbiology & Immunology)
We will develop a new strategy for targeting solid tumours by exploiting the overexpression of a coagulation factor expressed on a number of highly invasive solid cancers that are often refractory to chemotherapeutic treatment. T cells will be genetically modified using an antibody sequence against a tumour antigen which will be spliced to intracellular T cell signalling machinery. This grant will provide proof of principle that this approach can be used to destroy cancer.
St Joan’s Trust (Care of Elderly) & Southern Trust
Is sAPP protective against the toxicity of peptide A in Alzheimer’s disease?
Prof Warren Tate & Mrs Katie Peppercorn (Department of Biochemistry)
Sporadic Late Onset Alzheimer’s Disease (LOAD) is an increasing health, social and economic burden to New Zealand, and there are no effective therapies to reverse, or delay its onset. There is little general understanding of why some people develop the disease on ageing and others do not. Ultimately in the disease there is an increased concentration of toxic amyloid-beta (A) peptide aggregates that lead to destruction of neurones. Our studies show a neuroprotective brain protein, secreted amyloid precursor protein-alpha, (sAPP) has promise as a therapeutic agent for LOAD, as it can reverse memory loss in rats. We have preliminary data that sAPP may mediate its protective function by interacting with A, and it may also interact with the enzyme that produces A, BACE 1. Here we will investigate the neuroprotective functions of sAPP by determining whether it can reverse the aggregation of A, and interact with a specific toxic species to lower its concentration. We will determine whether sAPP interacts with the BACE 1 enzyme in vitro and can inhibit its enzyme activity. Since sAPP and A may be produced in different cellular compartments we will determine whether they are subsequently located together, perhaps in the lysosome.
Southern Victorian Charitable Trust
Investigating the spread of extended spectrum beta-lactamase (ESBL)-producing E. coli in Dunedin
Dr James Ussher, Dr Ambarish Biswas & Dr Xochitl Morgan (Department of Microbiology & Immunology)
Antimicrobial resistance, especially amongst members of the Enterobacteriaceae family, is a rapidly evolving global emergency. In Dunedin there has been an increase in the incidence of urinary tract infections caused by multi-drug resistant Escherichia coli that produce an extended-spectrum -lactamase (ESBL). It is unknown how these ESBL-producing E. coli are spreading. In this study we will use whole genome sequencing to determine whether the Dunedin isolates represent a clonal outbreak of one or more strains, or the dissemination of a mobile genetic element. This will inform future studies to define the mode of transmission of these multi-drug resistant pathogens and any possible public health intervention.
OTAGO COMMUNITY TRUST GRANTS (ADMINISTERED BY THE OMRF; $60,000)
We thank the Community Trust of Otago for their generous sponsorship that has made this possible.
Visualising cerebellar driven motor learning
Associate Professor Ruth Empson (Department of Physiology)
The cerebellum is part of the brain that integrates sensory information (from sensors that tell us about our environment) with movement information (eg. where to place our foot). In fact electrical activity of the cerebellum is critical for refining and controlling movements during everyday life, yet we understand little about how the cerebellum achieves this. Here we aim to leverage our recent success using genetically encoded reporters of neuronal electrical activity to determine the nature and timing of cerebellar synaptic activity during movement. These previously impossible experiments could radically change the way we think about how we refine and control movement.
Sorting out childhood leukaemia
Professor Ian Morison & Dr Robert Weeks (Department of Pathology)
Childhood acute lymphoblastic leukaemia (ALL), the most common childhood cancer, originates before birth. Accumulating evidence suggests that a distinct population of fetal lymphocytes might be the cell-of-origin of ALL. Childhood acute lymphoblastic leukaemia has a characteristic DNA methylation profile. We will use this profile to search for and enrich for normal lymphocytes in neonates that reflect the lineage from which ALL arises. Once isolated, this cell population will be characterised in detail and then studied to identify specific receptors and pathways that can be targeted for more effective and safer treatments.
Development of fluorescent ligands for cannabinoid type one receptor
Dr Andrea Vernall & Associate Professor Joel Tyndall (School of Pharmacy) & Associate Professor Michelle Glass (Department of Pharmacology & Centre for Brain Research – Auckland)
Cannabinoid type 1 receptor (CB1R) is a receptor occuring at high levels in the human brain and nervous system. This receptor holds huge promise as a way to treat neuropathic and inflammatory pain, liver disease, obesity, spasticity, neurodegenerative and psychological disorders. A much greater understanding of the exact role this receptor plays in important processes in the human body is required to unlock the therapeutic potential. Currently there are few tools available to study CB1R and none with the requisite properties to enable intricate biological experiments. This project aims to develop the first fluorescent ligand for CB1R, which can be used to better understand CB1R role in disease.
Annual Grants 2014
The Foundation is delighted to announce the outcomes of the Annual Grant round for OMRF and Community Trust of Otago sponsored grants. There were 38 applications, requesting $975,468. In total seven projects investigating aspects of medical research in Otago have been sponsored to a total of $144,503.
OTAGO MEDICAL RESEARCH FOUNDATION ($90,503)
Dr John Ashton & Associate Professor Rhonda Rosengren
Pharmacology & Toxicology: Synergy in cytotoxic and targeted drug combinations for ALK + lung cancer.
$16,000 (JN Lemon Trust)
Conventional therapy is usually ineffective at treating lung cancer, which kills more people than any other type of cancer, but in recent years a number of mutations have been found in some patients which can be
“targeted” with new generation drugs. One such mutation is in the “ALK” gene, which can be targeted with crizotinib, doubling life expectancy for patients. Pemetrexed is also a drug that can be effective in this type of
cancer. This project aims to test whether the two drugs in combination are more effective at killing cancer cells than either drug alone.
Dr Bill Hawkins
Chemistry: A new paradigm in drug design.
$17,000 (Southern Trust)
The current extreme bias in drug discovery to remove “reactive” functional groups from any lead molecule is depriving clinicians of more effective pharmaceuticals (e.g. lower dosing, extended half-life). Yet this bias is unnecessary. Numerous clinically used drugs whose mode of action was either identified after development, or developed well before current design practice, are dependent upon this reactivity, e.g., penicillin, aspirin. We will demonstrate that the rational incorporation of a “reactive” centre within a molecule, leading to a covalently bound drug, can be used as a new drug design strategy. As proof of principle, we will modify the clinically used blockbuster drug for the treatment of Alzheimer’s disease, Donepezil, from a reversible to irreversible inhibitor. Our work could transform the drug
development paradigm, resulting in new therapeutics to treat disease.
Dr Joanna Kirman
Microbiology & Immunology: Deciphering the memory T cell response to tuberculosis.
$15,517 (JN Lemon Trust)
The current vaccine against tuberculosis (TB) is ineffective and an improved vaccine is urgently required. In order to develop a new vaccine we must understand the memory immune cells that drive protection against TB. Most new TB vaccines are being designed to stimulate memory CD4 T cell development; however there is no solid evidence to suggest that this is appropriate. We propose to determine whether memory CD4 T cells are required for protection afforded by vaccination by specifically removing these cells after vaccination and before an infectious challenge. This study will aid the development of new TB vaccines.
Professor Iain Lamont
Biochemistry: Understanding and overcoming antibiotic resistance of Pseudomanas aeruginosa.
Pseudomonas aeruginosa is a species of bacterium that is a very common cause of hospital-acquired infections and also infects patients with cystic fibrosis or who are immunocompromised. The bacteria are intrinsically resistant to antibiotics, and become even more resistant during the course of prolonged infection, making infections difficult or impossible to treat. Collaborating researchers in Italy have recently identified a compound, fluorocytosine, that inhibits these bacteria from causing infection. The aims of this research are to understand how P. aeruginosa adapts during infection to have very high levels of antibiotic resistance, and how fluorocytosine works to byppass antibiotic resistance mechanisms and inhibit bacterial infection.
Dr Robin Simmonds
Microbiology & Immunology: Role of a bacteriocin-like inhibitory substance in the pathogenicity of group B streptococci.
$22,000 (Southern Victoria Charitable Trust)
Group B streptococci (GBS) can produce serious invasive disease in humans. Knocking out bliS, a gene encoding a recently discovered GBS endopeptidase, yielded strains of GBS attenuated for persistence in a mouse model. This is the first time an endopeptidase has been shown to play a significant role in the persistence of infection of an animal host by a major human pathogen. This study will establish a biochemical basis for the role played by BliS in the persistence of infection and allow us to establish the potential for therapeutic applications for BliS in the prevention of GBS infections in humans.
OTAGO COMMUNITY TRUST GRANTS (ADMINISTERED BY THE OMRF; $60,000)
We thank the Community Trust of Otago for their generous sponsorship that has made this possible.
Professor Alison Heather
Physiology: Defining estradiol’s bad effects on atherosclerosis: targeting safe HRT for women.
Calcification of artery walls increases the risks of heart attacks and strokes. Arterial calcification is a major medical problem affecting more than 60% of our population. Hormone-therapies that elevate estrogens (in women) or androgens (in men) can have adverse effects on heart disease, which our studies have shown can increase calcification. We now seek to define just how these hormone therapies adversely affect calcification in arteries so that more successful and safe therapies can be developed.
Dr Julia Horsfield, Dr Joseph Antoun & Professor Mark Hampton
Patholgy, Orthodontics Dental School Pathology, University of Otago, Christchurch respectively: A novel model for exploring the causes and treatment of craniofacial birth defects in children.
Cleft lip and cleft palate are common craniofacial birth defects. The incidence of cleft lip and/or palate (CL/P) is 1/700, and treatment over a lifetime can be very costly. The general view is that clefts are caused by a combination of genetic and environmental factors. In this research we want to determine how genetic and environmental causes of CL/P affect the growth and survival of cells contributing to the palate during embryo development. More importantly, we want to determine whether factors that enhance cell survival can actually rescue development of CL/P. The study will be done in zebrafish, an ideal animal model for these experiments. Our research could identify a potential for treatment with antioxidants to prevent CL/P in children, especially in families where there is an identified genetic or environmental risk.
Annual Grants 2013
The Foundation is delighted to announce the outcomes of the Annual Grant round for OMRF and Community Trust of Otago sponsored grants. There were 43 applications, requesting $1,128,850. In total seven projects investigating aspects of medical research in Otago have been sponsored to a total of $178,544. We thank the Community Trust of Otago for their generous sponsorship that has made this possible.
OTAGO MEDICAL RESEARCH FOUNDATION ($109,857)
Associate Professor Alex Mclellan
Microbiology & Immunology: Understanding how cancer spreads to the lymph nodes.
The first line treatment for most cancers is chemotherapy. An inevitable consequence of chemically-induced tumour cell death is the release of tumour cell fragments (vesicles) into the lymphatics. We have recently found that tumour vesicles bind to a specific receptor on lymph node macrophages and suppress the immune response – potentially allowing tumour escape. Using a novel model of metastatic disease, we will address our hypotheses that tumour vesicles interfere with the host immune response and enhance disease spread (metastasis). This project will assist in the development of intervention strategies to improve clinical outcome for cancer patients.
Dr Euan Rodger & Professor Ian Morison
Pathology: Does a New Zealand family hold the key to myelodysplastic?
We have discovered an abnormality in chromosome 5 of a patient with myelodysplastic syndrome (MDS), a common blood cancer of the elderly. Her sisters also have the chromosome 5 abnormality and have low neutrophil counts, which is sometimes a precursor to MDS. We hypothesise that the chromosome anomaly has disrupted genes required for normal neutrophil production and has led to MSD presented in the patient. We will use advanced DNA sequencing technology to pinpoint the exact location of the chromosome 5 abnormality and identify the disrupted gene(s). We anticipate that the genetic information obtained from this family will provide important insight into the cause of MDS.
Dr Sebastien Taurin, Dr Khaled Greish & Associate Professor Rhonda Rosengren
Pharmacology & Toxicology: Raloxifene micelles for the treatment of hormone refractory prostate cancer.
The survival of patients with hormone resistant prostate cancer is less than 25% over five years. Studies have highlighted the potential of raloxifene, a drug currently used for the treatment of breast cancer, in the control and treatment of prostate cancer. However, raloxifene is rapidly metabolised. To enhance raloxifene efficacy, we have encapsulated the drug in a nanomedicine carrier. Preliminary data show the superior toxicity of the nanomedicine containing raloxifene against prostate cancer cells. In this proposal, we aim to further evaluate our system in animals with prostate cancer to develop an efficient therapeutic alternative for prostate cancer treatment.
Dr Megan Wilson & Professor Ian McLennan
Anatomy: The molecular factors underlying male susceptibility to neurological disorders and injury.
Human male and female brains acquire subtle differences during embryonic development. This dimorphic development is influenced by circulating sexspecific hormones during fetal development such as anti-Müllerian hormone (AMH), a molecule that has recently been linked to autism. Many common childhood brain disorders have a strong male bias, including autism, and this is likely to be linked to differences in neurological development. Studies focused on brain anatomy have failed to determine the underlying features of susceptibility to these complex disorders. This new project is aimed at understanding how the sex of an individual affects differentiation of the brain, how AMH influences male brain development, and how AMH may be associated with an increased risk in males for neurological damage and disease.
OTAGO COMMUNITY TRUST GRANTS (ADMINISTERED BY THE OMRF)
Professor Cliff Abraham & Dr Joanna Williams
Psychology & Anatomy: Defining the novel contribution of microRNA to long-term memory mechanisms.
We have new evidence that small RNAs called microRNA may play a central role in controlling gene expression integral to long-term memory formation. MicroRNA are important negative regulators of protein syntheses, and we hypothesise that microRNA are gate-keepers controlling the translation of memory-related proteins. Testing this role, however, requires innovative approaches. Here, we will establish an easily manipulated experimental model system that can be used to alter the expression of specific microRNA in order to validate the link between microRNA and memory processes. This innovative study will shed new light on memory consolidation mechanisms, potentially identifying new therapeutic targets for neurological disease.
Professor Gregory Cook
Microbiology & Immunology: Succinate dehydrogenase: a new target for tuberculosis drug discovery.
Tuberculosis kills 1.7 million people annually and 10 million new cases of TB are diagnosed per year. Treatment of TB is difficult and new drugs are urgently required to combat increasing drug resistance and tolerance (clinically persistent) cells. The first anti-TB drug, bedaquiline, developed in 40 years was licensed in December 2012. Bedaquiline targets the F1FO ATP synthase, a nanosized ATP-generating motor that is fuelled by the respiratory chain of Mycobacterium tuberculosis. We have identified succinate dehydrogenase (SDH) as a key component of the respiratory chain and propose that SDH represents a potential target for inhibitor design. The goal of this proposal is to identify specific inhibitors of the mycobacterial SDH and test these inhibitors against M. tuberculosis during replicative growth and in non-replicated cells (hypoxic cultures) to validate SDH as a target for TB drug development.
Dr Elspeth Gold
Anatomy: Prognostic markers to determine prostate-specific antigen (PSA) failure in prostate cancer – a pilot study.
Optimal management of prostate cancer presents unique challenges because of the highly variable nature of the disease. Some men have organ-confined indolent disease that can be safely followed without immediate treatment, whereas others have aggressive prostate cancer and need immediate intervention. There are limitations with the current clinical variables used to predict the likelihood of cancer progression and they give little information concerning best treatment. Therefore we aim to identify a panel of biomarkers for use in prostate tissue sections to predict 5-year prostate-specific antigen (PSA) failure.
Annual Grants 2012
The Foundation is delighted to announce the outcomes of the Annual Grant round for OMRF and Community Trust of Otago sponsored grants. There were 22 applications, requesting $780,420 In total eight projects investigating aspects of medical research in Otago have been sponsored to a total of $177,131. We thank the Community Trust of Otago for their generous sponsorship of $60,000 that has made this possible.
OTAGO MEDICAL RESEARCH FOUNDATION ($119,700)
Dr Anita Dunbier
Biochemistry: Investigation of genes involved in breast cancer susceptibility and response to therapy.
Over three quarters of women diagnosed with breast cancer receive anti-oestrogen therapy. This project will investigate the role of three newly identified genes in breast cancer. We have found that these genes are turned on in breast cancer at the same time as the oestrogen receptor. They also appear to be involved in the way breast cancers respond to treatment. We aim to determine why these genes are turned on together and how this makes some breast cancers respond poorly to anti-oestrogen therapy. We hope this will help us to find better ways of treating breast cancer in the future.
Dr Rajesh Katare & Dr Regis Lamberts
Physiology: Why do females have a higher risk of diabetic heart disease?
Diabetic individuals are more prone to develop cardiac complications, like heart attacks. Diabetes damages cardiac cells directly, reducing their strength and viability. Diabetic cardiomyopathy starts very early, especially in females, and evolves to heart failure, causing disability and threatening patient’s life. However, the mechanisms behind this increased risk in females are unknown. Using an established type-2 diabetic mouse model, we will analyse the modulation of cardia-protective and -destructive genes at different duration of diabetes. We will integrate the molecular data with functional outcomes at each time point. The expected results will help to develop novel strategies for the treatment of diabetic cardiomyopathy.
Dr Anna von Zychlinski-Kleffmann
Biochemistry: Lipoprotein(a), new insights into a risk factor for heart disease.
Cardiovascular disease (CVD) is the leading cause of death worldwide. One major risk factor for premature CVD is a particle known as Lipoprotein(a) [Lp(a)], affecting one in five people. The exact function and role of Lp(a) in the development of CVD is unclear. However, we know there are differences between Lp(a) from healthy individuals and those with CVD. This study will establish protein signatures for different Lp(a) particles, so that these can be evaluated as biomarkers for CVD. Our project will provide a diagnostic and mechanistic insight into a poorly understood CVD-risk factor, with the potential to identify therapeutic targets.
Dr Adele Woolley & Professor Anthony Braithwaite
Pathology: Putting a novel prognostic marker for breast cancer through its paces.
Breast cancer is the leading cause of death for women. Despite considerable advances in diagnosis and therapy some breast cancers, particularly the highly aggressive types, remain difficult to treat. Identification of new ways to treat breast cancer is most important. Our published research has recently shown that the Y-box binding protein-1 (YB-1) is highly associated with high-grade and aggressive breast cancers. Therefore, targeting YB-1 provides a promising therapeutic strategy. In light of this we have developed a monoclonal antibody that can be used to specifically label YB-1. This proposal seeks funding to characterise this antibody so that it can be used as a reliable prognostic tool for breast cancer in the future and as a useful laboratory reagent.
Dr Yiwen Zheng & Professor Paul Smith
Pharmacology & Toxicology: Role of GABAB receptors in the dorsal cochlear nucleus in acoustic trauma-induced tinnitus
Chronic tinnitus is experienced by about 10% of the population and produces many detrimental effects on the quality of life. It has been suggested that tinnitus is generated in the brain by the hyperactivity of brain cells involved in hearing. This project will investigate, in a specific part of the brain thought to be important in tinnitus pathology, how the timing of the activation of one type of receptor involved in making neurons quiescent, contributes to the development of tinnitus. The results will provide a better understanding on how tinnitus develops and may lead to the development of target-specific therapies.
OTAGO COMMUNITY TRUST GRANTS (ADMINISTERED BY THE OMRF)
Assistant Prof Grant Butt
Physiology: Colonic sodium bicarbonate and inflammatory bowel disease.
Inflammatory bowel disease (IBD) is an inappropriate immune response to the normal intestinal bacteria. It involves both genetic and environmental effects that disrupt the interaction between the immune system, the commensal bacteria and the epithelial lining of the intestine, resulting in inflammation. We have identified a protein that transports sodium bicarbonate across cell membranes which is lost from the cells lining the inflamed colon. We propose that loss of this protein affects the viability of the cells lining the intestine, their ability to act as a barrier between the luminal bacteria and the immune system, and their ability to control the growth of the luminal bacteria through the secretion of sodium bicarbonate. We plan to test this proposal using the inflamed colon from an animal model of IBD, the interleukin 10-knockout mouse.
Assistant Prof Rhonda Rosengren
Pharmacology & Toxicology & Prof Helen Nicholson, Anatomy: Combination drug therapy for the treatment of aggressive prostate cancer.
Men diagnosed with prostate cancer that does not respond to hormone therapy have a poor prognosis. The currently available drugs have not significantly increased patient survival of this disease. This project will investigate a new combination therapy in order to develop more successful treatments for this aggressive cancer. We hypothesize that our drug combination, which kills 99% of prostate cancer cells in culture, works by isolating a key protein responsible for cell growth and cancer spread to other organs. This project tests that theory and also investigates whether the spread of prostate cancer can be reduced.
Jack Thomson Arthiritis Fund
The Foundation invites applications for grants to support medical research carried out in the Otago area or projects based in Otago. These are to be financed by income from a 2011 bequest to the Foundation by the late William John (Jack) Thomson.
In accordance with the wishes of Jack Thomson, applications are invited for medical research into the problems and
treatment of arthritis.
The health impact of osteoarthritis: health-loss burden and cross-instrument mapping
Assoc Prof Haxby Abbott & Dr Ross Wilson (Department of Surgical Sciences)
Economic evaluations of treatments for osteoarthritis require preference-based measures of healthrelated quality of life (HRQoL). The SF-6D is a widely used preference-based HRQoL index derived from the commonly-used SF-12 questionnaire. However, outcomes studies using the SF-12 often report only non-preference-based summary scores, which are not suitable for economic evaluations. This project will (1) estimate the impact of knee osteoarthritis on the six dimensions and overall score of the SF-6D, and (2) produce an osteoarthritis-specific mapping between SF-12 summary scores and the SF-6D. This will provide a tool for researchers to make SF-12 results usable for economic evaluations of osteoarthritis treatments.
Identification of oxypurinol transporters to decipher drug-drug interactions in gout treatment
Dr Andrew Bahn (Department of Physiology)
Gout is a painful inflammation of the joints due to .high serum uric acid (SUA) based mostly on an unhealthy diet. The gold standard for gout treatment is allopurinol. Once converted into oxypurinol it inhibits production of uric acid in the liver and lowers SUA. Gout has been associated with many comorbidities including hypertension, which requires adjustment of allopurinol dosage. These drugdrug interactions render gout treatment with allopurinol ineffective. As drug-drug interactions are based on competition of drugs at transport proteins we aim to identify oxypurinol transporters in the liver to resolve these drug-drug interactions and improve gout treatment.
Developing a patient-informed self-management programme for arthritis-related fatigue
Dr Gareth Treharne, Ms Roisin Hegarty (PhD Candidate) & Dr Tamlin Conner, (Department of Psychology) and Assoc Prof Simon Stebbings (Department of Medicine)
Fatigue is one of the most problematic symptoms of arthritis and impacts on the ability to meet daily personal, goals. Both clinicians and people with arthritis describe arthritis-related fatigue as difficult to overcome because current treatments are limited and overlook patients’ priorities. To address this shortcoming, we will conduct a two-phase research study to explore what patients want from a psychological intervention using the framework of Acceptance and Commitment Therapy (ACT). We will gather qualitative and quantitative data from participants with arthritis to gain insights into their unique perspectives on required support, and measure the impact fatigue has using daily diary methods. This will inform the later development of a patient-informed psychological intervention.
Are bacteria the key to driving inflammation in ankylosing spondylitis?
Assoc Prof Sarah Young & Ms Estelle Peyroux (PhD Candidate), (Department of Pathology)
The Spondyloarthritis diseases are thought to develop from a faulty immune response that drives an inflammatory response directed at joints. Ankylosing spondylitis (AS) is an arthritis affecting the spine that develops in young adults. Many AS patients have inflammatory bowel disease (IBD)-like symptoms and some go on to develop IBD. Previous studies undertaken in our laboratory looked at the role of gut bacteria in AS disease. We focused on a specialised immune cell, the dendritic cell, which directs specific immune responses to microbes. We made the unexpected observation that AS dendritic cells did not respond normally to particular gut bacteria. We believe this suggests immunity to these pathogens may be compromised. To determine how this altered dendritic cell response to bacteria is pertinent to AS inflammation we would now like to measure the corresponding effect on immune cell populations implicated in tissue destruction.
Dr Jayakaran Prasath, Dr Meredith Perry, Dr Cathy Chapple & Prof David Baxter1 & Dr Gareth Treharne2, School of Physiotherapy1 and Department of Psychology2
Title of Project: Early detection of hip/knee osteoarthritis to improve physical activity and self-efficacy – JT 336; Awarded December 2014; Project commenced February 2015.
Early diagnosis of hip/knee osteoarthritis (OA) and targeted intervention to increase physical activity by enhancing self-efficacy may provide short-term and long-term benefits in individuals with knee and hip OA. Although previous studies have been successful in identifying the prevalence of early OA in the community, these studies did not intervene to modify the disease progression or the symptoms. The aim of this two-phase research programme was to identify individuals with early signs of OA in the community and determine the feasibility of a targeted intervention programme. A random sample of 1440 people living in Greater Dunedin, New Zealand were identified from the New Zealand electoral roll and mailed a questionnaire to determine: (1) the prevalence of confirmed hip/knee OA, and undiagnosed hip/knee pain, and (2) their PA levels using the International Physical Activity Questionnaire. Of the 499 respondents, 50 individuals (10%) reportedly had physician-confirmed hip OA and 79 (15.8%) had reported confirmed knee OA. At least 25% (n = 128) had reported hip/knee pain which were either undiagnosed or due to an unknown reason. These 128 individuals were invited to participate in the further intervention phases of the study. Of the 79 individuals who expressed preliminary interest, 21 people finally enrolled into the intervention phases of the study. The remaining individuals either did not meet the criteria for the study, declined to participate or were unable to be contacted. The 21 participants were randomly allocated to one of the following three study groups: 6-week tailored physiotherapy intervention; 6-week tailored physiotherapy intervention + physical activity programme; usual care group. The primary measures of interest were: recruitment and retention rates, adherence to the intervention programme and acceptability of the intervention programme. The secondary measures were WOMAC (condition specific measure) and International Physical Activity Questionnaire measured at baseline, 6-weeks and 12-weeks.
Dr Daniel Cury-Ribeiro & Dr Gisela Sole, School of Physiotherapy
Title of Project: Shoulder muscle activity: a study on patients with pain-limited shoulder elevation – JT 335; Awarded December 2014; Project commenced March 2015.
Shoulder pain is the third most common musculoskeletal disorder, with a 1-month prevalence of 34%. Shoulder mobilisation improves pain and function for up to a week; however, our current research suggests that shoulder mobilisation leads to reduced activity levels in asymptomatic individuals. It is unclear what effect this technique has on patients with shoulder disorders. This study assessed the effect of shoulder mobilisation with movement on scapular and shoulder muscle activity levels between baseline and post-mobilisation periods. This is a repeated-measures, cross-over, participant-blinded, randomised trial. Thirty-six individuals with shoulder pain took part in the study, and attended two sessions, 24 hours apart, to avoid any carry-over effect. We monitored activity of scapular (upper and lower trapezius, and serratus anterior) and shoulder (supraspinatus, infraspinatus, middle and posterior deltoid) muscles. Baseline measurements (pain levels, range of motion and scapular and shoulder muscle activity levels) were taken at each experimental session, and participants received one of the two treatment conditions (mobilization or sham) in a randomised order. Data is currently being analysed. For updates on progress regarding findings from this study, please refer to: http://www.otago.ac.nz/physio/otago166002.html.
Title of Project: The role of pelvic girdle assessment to identify inflammation in patients with non-radiographic axial spondyloarthritis: a preliminary study – JT 334; Awarded December 2014; Project commenced February 2015.
The use of clinical tests for the sacroiliac joints to detect early axial spondyloarthritis (SpA) may enable a cost-effective alternative to identify early axial SpA. Our aim was to assess whether a set of clinical tests for assessing the sacroiliac joints presents acceptable sensitivity and specificity to identify active inflammation in patients with non-radiographic axial SpA. This is a construct validity study comparing the clinical tests with the reference standard – Magnetic Resonance Imaging (MRI) – to detect inflammation. Twenty participants with non-radiographic SpA participated in this study. Six clinical tests (Patrick’s Faber, Gaenslen´s, posterior pelvic pain provocation, palpation of the long dorsal sacroiliac joint ligament, active straight leg raise, and stork test on the support side) were applied in the participants along with a MRI evaluation of the sacroiliac joints. Ten of the twenty participants presented with active inflammation in the sacroiliac joints. The best individual performance to detect inflammation on the sacroiliac joint was the Patrick’s Faber test (sensitivity of 80%; specificity of 70%). When the tests presenting the best performances were combined (Patrick’s Faber, Gaenslen´s, and posterior pelvic pain provocation) the use of one and two out of three pain provocation tests (as positive) showed the best results; with the former presenting 90% of sensitivity and 60% of specificity, and the later 70% of both sensitivity and specificity. Based on this preliminary study, the use of pain provocation clinical tests for detecting early axial SpA is promising, and the need of future studies, is warranted.
Dr Daniel Ribeiro & Dr Gisela Sole
School of Physiotherapy: Can we optimize rotator cuff motor control? Exploring novel rehabilitation exercises for shoulder osteoarthritis treatment.
Shoulder osteoarthritis is a debilitating condition impacting daily living activities. Rotator cuff exercises are currently recommended at early stages of glenohumeral (shoulder joint) osteoarthritis. Recent studies, however, suggest little evidence for shoulder exercise as an effective intervention for improving function and reducing pain. Before designing and testing new interventions for shoulder osteoarthritis, it is important to identify whether these exercises optimise rotator cuff muscle movement. This study aims to quantify shoulder rotator cuff muscle activity during selected shoulder exercises, and to determine which exercises actually increase rotator cuff muscle activity levels.
Dr Stephanie Woodley, Professor Helen Nicholson & Dr Natasha Flack and Dr Cathy Chapple
Department of Anatomy & School of Physiotherapy: Can prehabilitation improve patient outcomes following hip joint replacement?
Osteoarthritis of the hip is a common chronic condition that affects the health and wellbeing of New Zealanders with approximately 7000 people undergoing hip joint replacement per year. Pre-surgical intervention (pre-habilitation) is beneficial for knee surgery but its effects on muscle strength, physical function and post-surgical recovery following hip joint replacement surgery have not been determined. This project will examine the feasibility and effectiveness of implementing a pre-habilitation exercise programme for patients awaiting hip replacement. It will also investigate whether ultrasound can be used as a reliable tool to assess hip muscle volume, a modifiable parameter with potential as an outcome measure. The pilot data from this project will inform the development of a multi-centre randomised controlled clinical trial to ascertain the benefits of pre-habilitation for patients undergoing hip replacement.
Associate Professor Warwick Duncan, Mr Diogo Zanicotti, Dr Dawn Coates & Professor Gregory Seymour
Faculty of Dentistry :Adipose-derived multipotent progenitor cells for bone regeneration on titanium devices.
New Zealand has an aging population with increased prevalence of obesity and physical inactivity, which has resulted in more people presenting with osteoarthritis. Advanced joint disease may be treated surgically by replacing joints with titanium orthopaedic devices. A successful outcome when placing orthopaedic devices is dependent on the presence of sufficient bone at the surgical site to anchor the prostheses. The implantation of so-called adult ‘stem cells’ or ‘multipotent progenitor cells’ (MPCs) has been advocated to directly regenerate missing tissue. Our research aims to investigate bone regeneration on titanium surfaces using adipose- (fat-) derived MPCs in a large animal model.
Dr Roslyn Kemp, Dr Michael Schultz
Microbiology & Immunology & Medicine: Spondyloarthropathy as a joint-specific manifestation of Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) and spondyloarthropathy (SpA) are autoimmune inflammatory diseases where immune cells cause pathogenic inflammation of the intestinal tract and spinal column, respectively. Over-reactive immune cells in genetically susceptible people respond to an environmental trigger, such as microorganisms, causing inappropriate inflammation and progression of disease symptoms. Although SpA primarily affects the spinal column, many patients also develop an inflamed intestine and symptoms resembling that of IBD. The cause of intestinal inflammation in both of these diseases is unknown and treatments are largely ineffective. We will investigate whether these diseases actually represent separate manifestations of the same disease and that this is initiated by the intestinal immune cells.
Associate Professor Tony Merriman & Associate Prof Sally McCormick, Associate Prof Jim Reid
Biochemistry & General Practice: Is type IV hyperlipoproteinemia causative of gout?
Gout is the most common form of arthritis affecting New Zealanders (-3% of Europeans and -6% of Maori). A primary cause is elevated levels of uric acid in the blood. The uric acid forms crystals in the joints and painful attacks of gout result from an inflammatory reaction of the immune system. However, not everyone with elevated uric acid gets gout. We will test whether a type of bad lipid called ‘very low density lipoprotein’ causes gout in high uric acid. People will be recruited from the Caversham Medical Centre. If our hypothesis is correct, treatment for gout with existing lipid-lowering drugs called fibrates may be possible.
Inaugural 2011 Grant
University of Otago arthritis research is being boosted through the awarding of the first grant from a new Otago Medical Research Foundation fund established to support research into the disease in Otago.
The inaugural $34,970 grant from the Jack Thomson Arthritis Fund will support a project titled:
Subtypes of inflammation in Rheumatoid Arthritis.
Professor John Highton of the Department of Medicine and two co-investigators will use the inaugural grant to study the role of certain inflammatory immune system molecules in rheumatoid arthritis. The researchers will investigate whether measuring expression of these molecules in the bloodstream and in joints can identify a subgroup of patients who suffer more severe forms of the disease.
About Jack Thomson
The generosity of the late William John ‘Jack’ Thomson will be of enormous benefit to Dunedin-based research into arthritis.
Mr Thomson, a former Dunedin chartered accountant and company secretary, died in Dunedin in September 2008 aged 83 and his estate has released a $2 million dollar bequest to the Otago Medical Research Foundation and as a result, the Foundation will administer the Jack Thomson Arthritis Fund.
Two grants in the vicinity of $35,000 to $40,000 each will be awarded annually from 2012 for specific research into the cause and treatment of arthritis.
Jack was a gentleman who was intensely interested in people,” Mr Davie said.
He was extremely generous with his time, helping many clubs and societies with honorary accounting and auditing services. And he had many friends from a wide cross-section of Dunedin society.
Jack was a successful fly fisher and was always keen to display photos of his latest catch or tell the stories behind the trophies on display at his home. He loved travel and had a passion for cricket, golf, tennis and bowls. He was also an avid photographer.
Mr Thomson attended Kaikorai and Maori Hill Primary Schools before three years at Otago Boys’ High School, 1939 to 1941. Having studied successfully at night for his accounting degree while employed by Provident Life Assurance with whom he spent 20 years, Mr Thomson worked for WEC Reid & Co (now Deloitte) and Tomkinson Wood Adams (now Wilkinson Adams Lawyers) before retiring in 1985.
He was a member of a number of associations and societies include the Dunedin Photographic Society, Balmacewen Bowling Club, Otago Anglers Club, Otago division of the Arthritis and Rheumatism Foundation, Otago Acclimatisation Society, Otago Golf Club and Pakeke Lions.
Jack suffered from debilitating arthritis in his latter years and often talked about how he would like to help with research into a disease which robbed him of his mobility but certainly not his enthusiasm for life.
The Foundation is delighted to be able to retain his name in perpetuity through his terrific generosity.
The Foundation invites applications for grants to support medical research carried out in the Otago area or projects based in Otago. These are to be financed by income from bequests to the Foundation by the late Alexia and James Laurenson, known as The Laurenson Awards.
In accordance with the wishes of the Laurensons, applications are invited for research in areas relating to the investigation and dissemination of knowledge concerning the effects of proper diet and/or drugs on human health.
Drug combination testing in an in vivo model of anaplastic lymphoma kinase (ALK) mutated lung cancer
Dr John Ashton (Department of Pharmacology & Toxicology)
Lung cancer is responsible for more deaths than any other cancer in New Zealand. It has recently been discovered that the anaplastic lymphoma kinase (ALK) receptor is overexpressed in 2-5% of lung cancer patients. While inhibiting this protein improves survival, resistance usually develops, within a year, frequently because of the overexpression of other proteins, such as IGF1-R. We seek to develop a model of metastatic lung cancer in order to test a novel combination strategy to prevent the development of resistance to ALK inhibitors. This will aid in the development of more effective treatment strategies for lung cancer patients.
Platinum (II) “click” antimicrobials: new weapons for fighting resistant microbes
Assoc Prof James Crowley (Department of Chemistry), Dr Heather Brooks (Department of Microbiology & Immunology) and Dr Gregory Giles (Department of Pharmacology & Toxicology)
Resistance of microbes to currently used antimicrobial drugs represents a major threat to human health. We propose to synthesise a small family of platinum(ll) “click” complexes and examine their antimicrobial activity against a range of resistant bacteria. Additionally the mode of action and cytotoxicity of these “click” metal complexes will be characterised. The resulting new class of metallo-antimicrobials could lead to antibacterial agents that display novel modes of action.
Ribose-cysteine supplementation: translating from animals into humans
Prof Sally McCormick (Department of Biochemistry) & Prof Samir Samman (Department of Human Nutrition)
Cardiovascular disease (CVD) is responsible for over 30% of deaths in New Zealand per year. Statin drugs reduce CVD death rates by reducing levels of low density lipoprotein cholesterol (LDL-C). However, statins alone do not adequately reduce CVD mortality, and cause side-effects in some individuals that preclude their use. Ribose-cysteine is a promising antioxidant compound that shows both antioxidant and LDL-C lowering properties in animals. We hypothesise that ribose-cysteine has the potential to protect individuals at risk of CVD. We propose to perform the first ribose-cysteine supplementation trial in humans to evaluate its effects.
Developing a novel therapeutic to protect hypertrophic hearts in acute ischaemic surgery
Assoc Prof Ivan Sammut, Dr Joanne Harrison & Dr Morgayn Read (Department of Pharmacology & Toxicology)
Over 800,000 surgical interventions requiring cardiac bypass are conducted globally each year. Whilst for the majority, the outcome is favourable, the procedure can inevitably result in damage to the heart through ischaemia-reperfusion injury. This exacerbates the patient’s condition and ultimately affects mortality. We have developed novel low-dose carbon monoxide releasing compounds that can prophylactically protect hearts from ischaemia-reperfusion injury. While this is a valuable finding, we wish to confirm that the same protection can be obtained in diseased hearts typically seen in bypass patients. We will trial our lead compound in a model of ischaemia-reperfusion conducted in enlarged hearts resulting from chronic hypertension. Ultimately this intervention will be developed as an adjunct therapeutic for use in cardiac surgery.
Assoc. Prof Ivan Sammut1, Dr Robert Walker & Assoc. Prof Gerrard Wilkins2, and Assoc. Prof Fiona McDonald & Dr Martin Fronius3, Department of Pharmacology1, Department of Medicine2 and School of Physiotherapy3
Title of Project: The cardio-renal syndrome: targeting aldosterone inhibition to reduce cardiac and renal injury – LA 340; Awarded December 2014; Project commenced April 2015.
There is now increasing awareness that heart attacks and heart failure can produce chronic kidney injury but the mechanisms are not well understood. Heart and kidney disease have common causative features, hypertension being one of the most significant. Combined kidney and heart disease has a worse outcome than heart failure alone (the cardio-renal syndrome). Using a hypertensive rat model, we have investigated the changes in cardiac, arterial and renal function and injury following a heart attack and how aldosterone blockade by spironolactone may modify the adverse effects. Reducing the impact of heart failure and kidney injury should improve survival.
Prof Ian Morison & Mr Robert Weeks, Department of Pathology
Title of Project: The mechanism of action of glucocorticoids revealed through changes in DNA methylation – LA 339, Awarded December 2014; Project commenced February 2015.
Glucocorticoids such as dexamethasone have been widely used for decades to treat a wide range of cancers. They are a vital component of chemotherapy especially for lymphoid cancers including childhood leukaemia, lymphoma and myeloma. Despite their importance, glucocorticoid use is limited by their numerous side effects and by the development of resistance. Many of the effects of glucocorticoids are mediated through changes in gene activity. Surprisingly, we have found marked changes in epigenetic marks on numerous genes in response to glucocorticoid treatment of a leukaemia cell line. Confirmation of these glucocorticoid-induced epigenetic changes and identification of the genes affected will help to identify strategies to target specific pathways to enhance treatment, bypass therapeutic resistance and avoid side effects.
Prof Sarah Hook, School of Pharmacy
Title of Project: Use of a dual COX/LOX inhibitor for treatment of cancer – LA 338; Awarded December 2014; Project commenced January 2015.
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to prevent inflammation. They have also been investigated for use to prevent and even treat cancer. The use of these drugs in cancer is still experimental and preliminary preclinical work from our group has shown that a new type of NSAID with a more broad-spectrum activity can treat cancer when used in combination with a cancer vaccine. This research project will eventually tailor the treatment regime, and how the drug is delivered, in order to optimise anti-cancer activity and patient quality of life.
Assoc. Prof Greg Anderson, Assoc. Prof John Reynolds & Dr Maggie Evans, Department of Anatomy
Title of Project: Hormonal restraint of hedonic eating behaviour – LA 337; Awarded December 2014; Project commenced July 2015.
Leptin’s hunger-suppressing actions in the hypothalamus are well characterised, yet the mechanisms by which leptin modulates the midbrain dopamine (DA) system to suppress hedonic feeding remain less clear. A subset of midbrain DA neurons express leptin receptors (Lepr), and direct leptin administration to the midbrain reduced food intake and suppressed DA neuron firing in rats, suggesting leptin may directly modulate DA neurons. To further explore whether direct leptin-DA signaling modulates appetitive behaviour, we generated transgenic mice in which Lepr were expressed exclusively in DA neurons. We then compared weekly body weight, daily food intake (standard chow diet), hyperphagic feeding (1-hr fully sated access to a high-fat high-sugar diet), and leptin-induced suppression of feeding between these LeprDAT mice and their wild-type (LeprCON) and LeprNULL littermates. As expected, both the LeprNULL and LeprDAT mice exhibited significantly increased body weight and food intake compared to the LeprCON mice. Interestingly, the LeprDAT mice exhibited significantly increased post-weaning body weight compared to the LeprNULL mice (3-8 weeks), yet no differences in adulthood body weight or food intake were observed. Furthermore, neither the LeprNULL nor LeprDAT mice exhibited a reduction in 4-hr food intake when treated with leptin (5 mg/kg) vs. saline, whereas the LeprCON mice exhibited a significant leptin-induced decrease in food intake. Lastly, LeprDAT mice appear to exhibit a blunted hyperphagic response compared to the LeprNULL mice, suggesting that their increased weight gain may be due instead to metabolic changes. While still preliminary, it appears direct leptin-DA signaling does indeed play a role in modulating appetitive behaviour.
Associate Professor Greg Anderson, Associate Professor John Reynolds and Dr Maggie Evans
Department of Anatomy: Hormonal restrant of hedonic eating behaviour
We all know how difficult it can be to resist a second helping of a delicious dinner, or turn down that piece of cake calling your name. However with obesity and its associated health problems on the rise, saying no to those tempting treats is becoming increasingly important.
Areas of the brain are known to have a physiological control over our body weight by stimulating and inhibiting food intake based on our body’s energy needs. However researchers have become aware that eating for pleasure rather than energy (hedonic eating) contributes a big part to the problem of obesity. With support from a Laurenson Grant (administered by the Foundation), Associate Professors, Greg Anderson, John Reynolds and Dr Maggie Evans are investigating the brain (neural) pathways involved in hedonic eating. Rewarding experiences cause the release of dopamine in certain areas of our brain, making us want to have these experiences again. Hedonic eating also causes the release of dopamine, triggering the neural reward pathways which stimulate overeating and the feeling of ‘food addiction’ that many people experience.
During their research project (funded in November 2014), Greg, John and Maggie will investigate how hormones involved in regulating the physiological control of eating, also affect an area of the brain containing dopamine cells. The hormones leptin and insulin normally signal our brain to say we don’t need any more energy (food). The research will focus on how leptin and insulin act in the brain to control release of dopamine during hedonic eating. The researchers believe that the release of dopamine while eating for pleasure is increased in obesity, motivating us to eat more, and that leptin and insulin might be the key to changing the feeling of reward our brain experiences and decreasing our desire to overeat.
This exciting research will hopefully take us a step closer to understanding how to break our ‘food addiction’ and step away from the dinner table!
Dr Khaled Greish and Dr Greg Giles
Pharmacology & Toxicology: Utilizing nanotechnology for improving anticancer therapy of pancratic cancer
Pancreatic cancer is a fatal type of cancer with the number of annually diagnosed cases almost equal to the annual death rate. The disease is even more lethal among Maori who demonstrate 50-100% higher incidence rate than non-Maori. Pancreatic cancer is especially difficult to treat because it has limited blood vessels to supply anticancer drugs. In this work we will test a new system made of two styrene maleic acid (SMA) nanomicelles. The first micelle will encapsulate a nitric oxide donor to cause vasodilation in tumor blood vessels and hence enhance the delivery of a second SMA micelle encapsulating the chemotherapeutic agent.
Associate Professor Dorothy Oorschot
Anatomy: Treatment of brain injury due to extreme prematurity: Is melatonin protective?
This translational research aims to investigate whether treatment with melatonin rescues the brain injury of extreme prematurity. Specifically, we will investigate if treatment with melatonin prevents the death of brain glia (i.e. pre-oligodendroglia), and prevents myelin and memory deficits, in an innovative, clinically relevant animal model. The animal model was developed by Associate Professor Oorschot and her research team at the University of Otago. This model was published1 in the prestigious international journal, the Journal of Neuroscience, in July 2013. A positive outcome would drive clinical trials to develop an effective treatment for brain damage due to extreme prematurity.
Associate Professor Rhonda Rosengren, Dr Sebastien Taurin and Dr Elspeth Gold,
Pharmacology & Toxicology & Anatomy: Using raloxifene in a drug combination for the treatment of metastatic hormone refractory prostate cancer
Men diagnosed with prostate cancer that does not respond to hormone therapy have a poor prognosis and the current treatment options have not significantly increased patient survival. This project will investigate the ability of a new combination therapy, which we have recently developed, to suppress prostate tumor growth in vivo. We already know that this drug combination kills 99% of prostate cancer cells in culture and works by isolating two key proteins responsible for cell growth and cancer spread to other organs. This project examines the next critical step, which is to determine whether these effects in cell culture will also occur in a mouse model of aggressive prostate cancer.
Dr James Crowley and Dr Gregory Giles
Chemistry & Pharmacology & Toxicology: Exploiting palladium nanocages for cisplatin drug delivery.
Every year in New Zealand, cancer affects around 18,000 new patients, and kills >8,000 people. Cisplatin is a widely used anti-cancer agent which is very effective against a variety of tumors. However, this platinum based drug has two major drawbacks, namely general toxicity (leading to undesirable side effects) and drug resistance. We have synthesized novel nanoscale cage molecules that are able to bind two molecules of cisplatin within their central cavity. The aim of this research is to show that these palladium nanocages can be exploited to deliver cisplatin drugs selectively to tumor sites thereby increasing the efficacy and safety of these platinum drugs. This could potentially result in new, more effective therapeutic protocols for cisplatin administration in the clinic.
Associate Professor Graeme Hammond-Took, Associate Prof Anthony Poole and Dr Koji Yamanoto, (Honorary Research Fellow)
Medicine: The effects of lithium on rat sciatic nerve recovery following crush injury
Demyelination (loss of the myelin sheath, the insulating layer around many nerve fibres) is a prominent feature of diseases like multiple sclerosis and Guillain-Barre syndrome. The drug lithium has recently been shown to stimulate both myelin formation and elongation of primary cilia, small sensory “antennae” found on most cell types including myelinating Schwann cells. We will study peripheral nerves following crush injury, with and without lithium treatment, using confocal and electron microscopy. Staining for ciliary proteins will be used to determine the role of primary cilia in myelin repair and the potential for lithium therapy in myelinating disorders.
Dr Shakila Rizwan and Associate Professor Ben Boyd (Monash University)
Pharmacy: Cubosomes: Novel lipid-based particulate carriers to improve delivery and efficacy of anti-epileptic drugs in drug-resistant epilepsy.
Epilepsy is a common brain disorder with up to 40% of sufferers failing to achieve good seizure control. One possible reason for treatment failure is that high enough levels of anti-epileptic drugs (AEDs) don’t reach the brain. A promising strategy to increase brain AED concentrations is by incorporating them in carriers. The aim of this study is to investigate whether cubosomes, a novel lipid based carrier will facilitate the uptake of AEDs into the brain.
Dr Shelia Sheaff & Associate Professor Patrick Manning
Human Nutrition & Medicine: Diagnosing mild iodine deficiency in New Zealand adults.
Iodine is required to make thyroid hormones needed for normal growth and development, particularly of the brain. A lack of iodine in the diet is still one of the most common nutrient deficiencies in the world today. From the mid 1990s, mild iodine deficiency re-emerged in New Zealand prompting the government to make the addition of iodised salt to bread compulsory in 2009. However, people who eat little or no bread remain iodine deficient. Currently, we can only measure iodine deficiency in groups of people. This project will determine if a blood component called thyroglobulin can be used to diagnose mild iodine deficiency in adults
Professor Gerald Tannock and Associate Prof Richard Gearry & Professor Andrew Day (Medicine Christchurch)
Microbiology & Immunology & Medicine: Measuring the temporal impact of exclusive enteral nutrition on gut microbiota and urinary metabolite profiles of Crohn’s disease patients: a pilot study.
The bacteria that live in the bowel appear to drive the chronic inflammation seen in Crohn’s disease. The composition of the bacterial collection in stool of newly diagnosed, young adult, Crohn’s disease patients will be determined and correlated with urinary chemical profiles. Changes in these bacterial and chemical profiles, resulting from consuming a fluid formula as exclusive enteral nutrition (EEN), will be recorded. This pilot study will reveal whether EEN changes the bacterial content of the bowel with improved clinical outcomes, and whether the products of bacterial metabolism excreted in urine are altered consequently and could be used as indicators of successful treatment.
Dr Andrew Bahn and Associate Professor Lisa Stamp
Department of Physiology & Department of Medicine: Impact of furosemide on uric acid homeostasis (synthesis and transport) in humans.
Elevated serum urate (SU) levels in humans are required for the development of gouty arthritis. Lowering SU to <0.36mmolfL is critical for the long-term management of gout. The most common treatment to reduce SU is allopurinol, an inhibitor of xanthine oxidase (XO). Hypertensive gouty patients are frequently treated with furosemide, which interacts with allopurinol making urate lowering more difficult. The molecular background of this effect is unresolved. AMP-kinase (AMPK) is a regulator of urate transport in the kidney, which is the main contributor to SU homeostasis. We aim to examine the molecular effect of furosemide on XO and AMPK to understand this drug-drug interaction. This study will help to improve treatments for patients with gout receiving furosemide.
Dr Kirsten Coppell
Department of Medicine: A description of obesity related liver damage and associated disorders in the adult New Zealand population- Results from the 2008/2009 New Zealand Adult Nutrition Survey.
The prevalence of obesity dramatically increased in New Zealand between 1997 and 2008/09 from 17.0% to 27.7% in males and from 20.6% to 27.8% in females. Remaining blood from the 2008/2009 New Zealand Adult Nutrition Survey (ANS) provides an opportunity to describe the epidemiology of two increasingly important conditions associated with obesity and the metabolic syndrome: non-alcoholic fatty liver disease (NAFLD) and hyperuricaemia (elevated serum urate). Both conditions are reported to be high in other western countries (30% for NAFLD and 20% for hyperuricaemia), and can progress to more serious health problems. Overconsumption of fat and soft-drinks are important dietary factors contributing to the development of both conditions. Liver function tests and serum urate will be measured, and results analysed with data collected as part of the ANS.
Dr Khaled Greish and Associate Professor Rhonda Rosengren
Department of Pharmacology & Toxicology: Utilising nanotechnology for producing effective anticancer therapy against breast cancer
In New Zealand, every year Breast cancer affects around 2500 new patients, and kills more then 600 patients. One third of breast tumors lack a protein called the estrogen receptor, resulting in lack of effective management, leading to aggressive recurrence and metastasis. We have synthesized novel curcumin derivatives with high efficacy against this type of cancer. Within the scope of this grant we aim to demonstrate selective delivery of these novel drugs to breast tumors models with nanotechnology. Nanotechnology can not only increase the efficacy but also the safety of our compounds, and potentially result in a clinical drug for those patients.
Dr Regis Lamberts and Dr Peter Jones
Department of Physiology: How do blood pressure stimulating-drugs affect the diabetic heart?
Diabetes is often associated with an increase in heart complications, especially during surgery. Heart function is governed by calcium, which is controlled by calcium handling proteins and catecholamines (adrenaline). In diabetes the control of the heart by these factors is reduced. We will measure changes in calcium handling proteins in response to catecholamines in heart biopsies from diabetic patients, and in hearts from diabetic animals in which we will also relate this to functional measurements. This will yield crucial knowledge of why catecholarnines poorly regulate the diabetic heart and help to develop new strategies to optimise the use of catecholaminergic drugs during surgery.