Annual Grants

ADEPT MACTODD Charitable Trust (Funder)

Cracking the secrets of senescence to reveal mechanisms of ageing and disease

Principal investigator: Dr Erin Macaulay, Department of Pathology, University of Otago.

Co-investigators: Dr Chi Lynch-Sutherland, Children’s Medical Research Institute, Sydney, NSW, Australia, Dr Xaviour Walker, Department of Medicine, University of Otago.

As we age, our cells undergo a process where they stop dividing and release harmful signals. This process is called senescence and plays a key role in ageing and age-related diseases like cancer and heart disease. With the increasing number of ageing individuals and rising prevalence of age-related conditions, understanding the mechanisms behind senescence is urgent. Our research focuses on a genetic disorder where cells avoid senescence and form tumours. By studying senescence in these cells, we aim to uncover its secrets and develop novel strategies and treatments that promote healthy ageing and alleviate the burden of age-related conditions on our healthcare system. 

Aotea Holdings Group Limited (Funder)

Breaking up free living sedentary time in the evening with regular activity breaks: A feasibility study 

Principal investigator: Dr Meredith Peddie, of Human Nutrition, University of Otago  

Prolonged periods of sitting in the evening, and sleeping for less than 7 hours a night, are both associated with an increased risk of developing several diseases, such as heart disease and type 2 diabetes. Our group was among the first to show, in a laboratory setting, that regularly interrupting prolonged periods of prolonged sitting with brief bouts of activity in the evening improved blood sugar uptake, and sleep duration both of which can reduce the risk of developing these diseases. To date, no study has investigated whether people would be willing to break up their sitting time in the evening as part of everyday life. Therefore, this study will explore the feasibility of interrupting sitting time in the evening with body weight resistance exercises in a real-life setting. 

Aotearoa Gaming Trust (Funder)

Investigating genomic alteration in tumour cells under the pressure of anti-tumour immune responses

Principal investigator: Dr Kunyu Li, Department of Pathology, University of Otago.

Co-investigators: Prof Antony Braithwaite and Prof Mike Eccles, Department of Pathology, University of Otago.

Despite the recent success of some cancer treatment strategies, most cancer patients develop cancer reoccurrence after the initial response to the treatments. There is evidence suggesting that these cancer cells had mutated, adapted, and resisted to the treatments in order to survive. In this research, we aim to understand how immune response might influence the mutation of cancer cells that allows them to develop resistance to subsequent killing by the immune system, using an animal model of melanoma. The findings of this research contribute to the improvement of treatment outcomes for cancer. 

OceanaGold (Funder)

A neuroendocrine role for GIP in the treatment of obesity

Principal Investigator Dr. Alexander Tups, Associate Professor, Department of Physiology, University of Otago

Co-investigator Dr. Geke Aline Boer, Research Fellow, Department of Physiology, University of Otago

The prevalence of obesity is increasing worldwide and is associated with serious health problems and mortality. An important cause of obesity is an imbalance between energy intake through food consumption and energy expenditure. Glucose-dependent insulinotropic polypeptide (GIP) is secreted from the gut when we consume food and there are indications that GIP may signal through regions of the brain to influence food consumption and metabolism. Using a genetically modified mouse model, we will determine how GIP signals in the brain to help maintain a healthy energy balance. Results of these studies will aid future development of obesity therapies.

Otago Community Trust (Funder)

Understanding the host immune landscape of bacterial skin infections

Principal investigator: Dr Daniel Pletzer, Department of Microbiology and Immunology, University of Otago.
Co-investigators: Dr Rajesh Lamichhane & Dr Sam Taylor Wardell, Department of Microbiology and Immunology, University of Otago.

The skin is the body’s defence barrier that protects from physical and chemical damages as well as prevents the entry of infectious agents. Damage to skin integrity can result in various skin diseases caused by bacterial microorganisms. In addition, the presence of different types of bacteria at the same time can lead to more severe infections that make effective treatment difficult. Our study will investigate small changes in host immune cells in response to individual and mixed bacterial infections to understand how the presence of one or more bacterial species alter the host immune response.

Otago Community Trust (funder)

Targeted use of combination treatments in inflammatory bowel disease

Principal investigator: Dr Nicholas Fleming, Department of Pathology, University of Otago.

Co-investigator: Prof. Michael Schultz Department of Medicine, University of Otago.

Inflammatory bowel disease (IBD) is a significant and growing health burden for Aotearoa/New Zealand, which currently affects at least 20,000 Kiwis. IBD patients have a limited range of treatments available, to which they have greatly varying responses. Recently a new group of potentially useful medications was discovered, but it is expected that they may need to be combined with existing options to be effective. Moreover, evidence suggests that they may work in some patients but not others due to a common genetic variation within our population. In the supported work, we established that the genetic variation alters the severity of IBD, and then we established that one of the candidate drugs worked better than another in this setting. Going forward, these findings will help us definitively test the drugs in combination with existing treatments and will help us better understand IBD.

ADEPT MACTODD Charitable Trust (Funder)

Novel, cost effective solutions for equitable tumour mutational burden testing in NZ

Lead Researcher: Dr Robert Day, Department of Biochemistry, University of Otago

Cancer is New Zealand’s biggest killer and targeting effective therapies to patients who are likely to benefit will improve outcomes. The number of DNA changes in a tumour can predict how well a person will respond to therapies that induce the patient’s own immune system to attack the cancer. Current genomic profiling methods used to estimate mutational changes are costly, time consuming and inaccessible to many New Zealanders.  This project successfully adapted technology  that will make measurement of DNA changes more accessible and inexpensive.  The study also generated evidence suggesting that this approach has the potential to facilitate improved and equitable cancer care.

Aotea Holdings Group (Funder)

Using carbon monoxide to prevent doxorubicin-induced cardiotoxicity

Lead Researcher: Dr Abigail Bland, Pharmacology & Toxicology, School of Biomedical Sciences, University of Otago

Doxorubicin remains one of the most commonly used chemotherapies for cancers, including triple negative breast cancer. Although doxorubicin provides effective cancer treatment, it can inadvertently produce severe heart damage. However, reducing the dose or discontinuing treatment risks accelerated tumour progression and premature death. As low doses of carbon monoxide have been shown to be cardioprotective, this project will explore a safe carbon monoxide-releasing molecule to prevent heart damage from doxorubicin.

Margaret Begg Charitable Trust (Funder)

How does mutation of cytochrome C cause low platelets?

Lead Researcher: Associate Professor Elizabeth Ledgerwood, Department of Biochemistry, University of Otago

Platelets are small blood cells that are essential for clotting and repair of damaged blood vessels. When people have low platelets (e.g. following chemotherapy) they require platelet transfusions. Because donated platelets have a short shelf life, scientists worldwide are trying to develop new ways of producing platelets. This requires us to fully understand how platelets are normally made. Studying people with inherited low platelets helps us understand how human platelets are made. We have identified NZ families with mutations that cause low platelets. We will determine how these mutations change platelet production. By enhancing our understanding of platelet formation, we will help international efforts identifying new therapeutic approaches for treating low platelets.

Aotearoa Gaming Trust (Funder)

Switching from tolerance to resistance: are ncRNAs the missing link?

Lead Researcher: Dr Glen Reid, Department of Pathology, Dunedin School of Medicine, University of Otago

Cancer treatment has been revolutionised by targeted therapeutics which act by blocking the pathways that drive cancer. However, despite initial dramatic results, relapse is inevitable and a major clinical problem. Recent studies have identified a rare population of drug-tolerant cells as being largely responsible for relapse. These cells evade therapy and become permanently resistant by acquiring mutations. Here we will determine how drug-tolerant cells gain the mutations which allow them to permanently evade therapy. By understanding how drug-tolerant cells become permanently resistant our long-term goal is to prevent their contribution to relapse and improve treatment outcomes for cancer patients.

OceanaGold (Funder)

Role of a cytochrome oxidase in making Pseudomonas aeruginosa tolerant to antibiotics

Lead Researcher: Professor Iain Lamont, Department of Department of Biochemistry, University of Otago

Pseudomonas aeruginosa is an extremely problematic bacterial pathogen, causing a wide range of infections. Antibiotics often fail to eradicate the bacteria. During infections P. aeruginosa often exists under conditions where little or no oxygen is present. We have identified a protein that helps the bacteria to resist a key antibiotic, tobramycin, during growth in the absence of oxygen. In this research we will investigate how this protein helps the bacteria resist tobramycin. The research could lead to more reliable methods for predicting which antibiotics will be effective in treating Pseudomonas infections, and in the long-term much-needed new tools for treatment.

Otago Community Trust (Funder)

A NZ family to reveal pathways of B-cell immunity and cancer

Lead Researcher: Professor Ian Morison, Department of Pathology, Dunedin School of Medicine, University of Otago

Naturally occurring genetic variants within families provide an opportunity to reveal the pathways of human disease. We are studying a NZ family with Otago members who have a specific genetic mutation that predisposes them to autoimmune destruction of their own platelets, but also appears to predispose them to cancers of the immune system. Two members of the family have, at a young age, developed cancers of immune cells. While mouse experiments have shown disturbed immune cell development, humans are different and this family provide an opportunity to determine the role of the affected gene (MYB) in human health and disease

Otago Community Trust (Funder)

Development of a dual action molecular targeting construct for the treatment of ADPKD

Lead Researcher: Professor Mike Eccles, Department of Pathology, Dunedin School of Medicine, University of Otago

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited fatal diseases in humans, affecting about 1 in 1000 people. Multiple members of one family can be afflicted, with devastating consequences. Tolvaptan is the only available treatment for ADPKD, although it has severe side-effects. We, and others, have shown that lowering the expression of certain genes that promote cyst growth can slow disease progression. In this proposal we will test a molecular approach that targets two of these gene products at once, PAX2 and miR-17. Developing ADPKD-specific treatments is the key to slow cyst formation and delay kidney failure.

Otago Community Trust (Funder)

Examining the relationship between epicardial fat and heart health of post- menopausal women

Lead Researcher: Dr Hamish Aitken-Buck, Physiology, School of Biomedical Sciences (BMS), University of Otago

The thickness of fat surrounding the heart and the risk of heart disease both increase markedly in women after menopause. How changes in heart fat might contribute to heart disease processes is unknown. Using human samples, this project aims to determine whether fat deposits and formation of scar tissue within the hearts of post-menopausal women is linked to differences in fat metabolism and expression of pro-scarring factors within heart fat. The insights gained from this research will fill important gaps in the understanding of why a woman’s heart becomes more susceptible to disease after menopause.

ADEPT MACTODD Charitable Trust (Funder)

Circulating microRNAs as prognostic indicator of ischemic heart disease

Lead Researcher: Associate Professor Rajesh Katare, Department of Pathology, University of Otago

In patients with chronic heart disease, the transition from a clinically stable disease to an acute life-threatening event remains unpredictable. Echocardiography is used to determine changes in cardiac function that requires patients visiting a specialty centre, which is expensive and infrequent. Our on-going clinical study identified micromolecules released by the diseased heart into the circulation. We aim to complete the first five-year follow-up study to determine whether changes in the level of these circulating micromolecules correspond to changes in cardiac function, as measured by echocardiography. If these blood micromolecules indicate heart disease, patients can be tested frequently by their local doctor to monitor progression of disease and their response to treatment.

Aotea Holdings Group (Funder)

Bacterial products that can improve anti-tumour immune responses

Lead Researcher: Professor Roslyn Kemp, Department of Microbiology & Immunology, University of Otago

Aotearoa Gaming Trust (Funder)

BARD1: a valuable new marker to predict the outcome of triple-negative breast cancer patients

Lead Researcher: Dr Magda Ratajska, Department of Pathology, University of Otago

Drugs targeting specific mutations improve patients' outcome in several cancer types, including breast cancer. Women with triple-negative breast cancer (TNBC) do not express HER2 or estrogen/progesterone receptors, therefore they are unable to benefit from hormonal or targeted therapy. However, TNBC is more common in patients with BRCA1 mutations and they respond well to PARP inhibitor drugs (PARPi). Patients with mutations in other genes, like BARD1, can also benefit from PARPi. Here, we will characterize TNBCs with BARD1 alterations and explore the molecular features associated with patient survival. This research might help in identifying the population of patients with the greatest potential benefit from PARP inhibitor.

Margaret Begg Charitable Trust (Funder)

Repeating the past: a role for early developmental genes in malignancy

Lead Researcher: Dr Erin Macaulay, Department of Pathology, University of Otago

Genes that promote life may also drive death. We have discovered a unique set of genes in melanoma (a dangerous skin cancer) that are also expressed in tissues of early human development. Our recent data shows that these “early developmental” genes become reactivated in melanoma, and potentially other cancer types. Importantly, these genes are not expressed in any other healthy adult tissue, so we could target them specifically in the cancer cells. This would greatly reduce side effects for patients, because their healthy cells won’t be affected. Therefore, these genes may be useful as new melanoma therapies, which are desperately needed in New Zealand.

OceanaGold (Funder)

How does lack of oxygen increase antibiotic resistance in Pseudomonas aeruginosa?

Lead Researcher: Professor Iain Lamont, Department of Biochemistry, University of Otago

Pseudomonas aeruginosa is an extremely problematic bacterial pathogen, causing a wide range of infections. Antibiotics often fail to eradicate the bacteria. During infections P. aeruginosa often exists under conditions where little or no oxygen is present. We think this is one reason why antibiotics don’t work properly. In this research we investigated how well Pseudomonas tolerates two key antibiotics, tobramycin and colistin, when oxygen is not available. Our results showed that less tobramycin gets into the bacteria, making this antibiotic less effective, when the bacteria grow in the absence of oxygen. The effectiveness of colistin was unchanged when the bacteria were deprived of oxygen. The research could lead to better tools for predicting which antibiotics will be effective in treating Pseudomonas infections, and for improving patient treatment through co-administration of oxygen with antibiotics.

Otago Community Trust (Funder)

Rurality, deprivation and ethnicity: their intersection and impact on health

Lead Researcher: Associate Professor Gabrielle Davie, Department of Preventive and Social Medicine, University of Otago

Unfair differences in health between socioeconomic and ethnic groups exist in NZ. It is currently less clear whether similar rural-urban differences exist and whether poor health outcomes can be explained by the socioeconomic and ethnic composition of rural areas. Obtaining clarity on this is essential to appropriately informing health policy, planning, and the delivery of health services in rural areas. Using a recently completed and robust method of classifying areas as rural or urban, this research will examine the overlap between ethnicity, socioeconomic deprivation and rurality and the influence that these factors have on health outcomes and inequities.

Otago Community Trust (Funder)

Breast milk nutrient composition in healthy mother-infant pairs

Lead Researcher: Dr Lisa Daniels, Department of Medicine, University of Otago

Despite breast milk being the main food for 69% of babies until about 8 months of age, we don’t currently know how much breast milk they are consuming, or what the nutrient composition is, which makes it challenging to understand what intakes are required for health. In our First Foods New Zealand study, we are investigating how much breast milk New Zealand babies are consuming; this application is an extension of this work to determine the related nutrient composition of that breast milk from mother-infant pairs. Combining these novel data will yield new understanding about nutrient intakes at this very important time of life.

Otago Community Trust (Funder)

Developing Better Therapies for Metastatic Oestrogen Receptor Positive Breast Cancer

Lead Researcher: Dr Anita Dunbier, Department of Biochemistry, University of Otago

Over three quarters of breast cancer patients diagnosed in New Zealand present with hormone-sensitive disease and are treated with anti-oestrogen therapy. Unfortunately, many develop resistance to this therapy and spread to other parts of the body leading to significant loss of life. Better treatments for these patients are urgently needed. Our previous work suggests that anti-oestrogen therapy may make tumours more responsive to treatment that stimulates the immune system. We plan to test whether immune therapies in combination with anti-oestrogen therapy can be effective against cancers that have metastasised to other parts of the body.

JN Lemon Charitable Trust (Funder)

Streaming before dreaming: how do electronic media influence sleep in children?

Researcher: Professor Rachael Taylor, Department of Medicine, University of Otago

Using electronic media before bed leads to poor sleep, which in turn, impacts how well children function the following day. We don’t currently know how much children are using electronic media in the evening (including after “lights out”), whether more interactive behaviours like gaming are worse than reading a book on your iPad, or whether using multiple devices at the same time have different effects on sleep in 10- 12 year old children. By using wearable and stationary cameras to objectively measure screen behaviours, we will be able to answer these questions, providing much-needed information for developing appropriate sleep health guidelines.

Aotea Holdings Group (Funder)

How much breast milk are New Zealand infants actually getting?

Researcher: Dr Lisa Daniels, Department of Medicine, University of Otago

Surprisingly little is known about what infants consume during their remarkable journey from drinking a 100% milk diet at birth, to eating the same foods as their family around their first birthday. In fact, even though breast milk is the main food for 69% of New Zealand babies until at least 8 months of age, we don’t even know how much breast milk they are consuming. The First Foods New Zealand (FFNZ) study has been funded by the HRC to find out what and how New Zealand babies are being fed, but additional sample collection is required for accurate measurements to be made of the amount of breast milk babies are getting. This funding will enable FFNZ to collect these data.

Otago Community Trust (Funder)

Does "Closing the Loop" improve sleep in those living with type 1 diabetes?

Researcher: Associate Professor Ben Wheeler, Department of Women’s & Children’s Health, University of Otago

People living with Type 1 Diabetes need to ensure their blood glucose is well controlled to avoid short and long-term complications. New technology (undergoing clinical trials) acts like an artificial pancreas to do this. Our preliminary evidence that sleep improves using this technology will be explored further in a new trial of 60 patients; measuring and asking about their sleep, alongside interviewing a subsample about their experiences using this technology specifically related to glucose management and everyday living. The research will provide important information on the benefits of this state-of-the-art technology for improving sleep with wide implications for overall health.

Otago Community Trust (Funder)

The Role of the Epithelial Sodium Channel (ENaC) in Breast Cancer Metastasis

Researcher: Fiona McDonald, Department of Physiology, University of Otago

Breast cancer is the leading cause of death in women worldwide, with 90% of these deaths attributed to metastasis, the process whereby cells from the primary tumour migrate and invade a secondary site in the body. Our preliminary data has suggested that the epithelial sodium channel (ENaC), an ion channel with a role in the regulation of blood pressure, has a significant impact on key metastatic characteristics. Our research investigates the role ENaC may play in metastasis with a particular focus on how ENaC affects the speed of growth of breast cancer cells.

Margaret Begg Charitable Trust and Friends of the Foundation (Funder)

Understanding and targeting drug tolerance in lung cancer to prevent drug resistance

Researcher: Dr Aniruddha Chatterjee Department of Pathology University of Otago

Cancer drugs that target specific mutations have improved survival for some patients, but responses are usually short-lived and patients invariably suffer relapse with drug-resistant tumours. Previously it was thought that this was due to traditional Darwinian selection of pre-existing mutant cells. However, recently it has been discovered that some cancer cells in a tumour are able to ‘epigenetically’ adapt to a drug-tolerant state. These persistent cells then give rise to mutants during continued treatment. Whether they exist prior to treatment, are induced by the drug, or both, is not well understood. Here we have analysed the epigenetic characteristics of these cells to better identify and target them. These results provide strong evidence that drug-tolerant cells have a distinct epigenetic signature. Future work will be aimed at determining the causal role of this signature in the acquisition of the drug-tolerant phenotype and how these might be exploited clinically.

The Southern Trust (Funder)

Host response to mono- and polymicrobial infections in a mouse skin abscess model and treatment with an immunomodulatory peptide

Researcher: Dr Daniel Pletzer, Department of Microbiology & Immunology University of Otago

Infectious diseases have traditionally been associated with individual microorganisms. However, recent progress in sequencing technologies revealed that many infections are mixed where two or more species of microbes occupy the same niche. This increases the severity of the infection and complicates treatment strategies. It is important to understand how the body reacts to individual and mixed infections to identify better interventions for complex infectious diseases. Our research will address this gap, investigating the response of a mouse host to various infections and we will investigate a novel treatment strategy, based on a small synthetic peptide, for mixed infection.

ADEPT-MACTODD Trust (Funder) 

Delivery of a micro RNA based nanoncomposite powder for treatment of Chronic Obstructive Pulmonary Disease

Researcher: Dr Shyamal Das, School of Pharmacy, University of Otago

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. In New Zealand, it has the highest mortality of all respiratory diseases and is highly prevalent in Māori. However, current treatment of COPD has only limited efficacy. The aim of this project was to develop a novel gene therapy for COPD using an inhaled treatment. We produced formulations containing a combination of molecular regulators and tested them in the lab. This type of gene therapy has the potential to revolutionise the treatment of COPD.

OceanaGold/Otago Medical Research Foundation (Funder)

Immunity to measles in immunised young adults - is it waning and does it matter?

Researcher: Professor Peter McIntyre, Department of Women’s & Children’s Health University of Otago

Measles is so infectious that despite high vaccination outbreaks can occur when the virus comes in from overseas – as seen in NZ in 2019 with over 2,000 cases. All commencing health science students at Otago have blood tests and more than 20% have low antibodies to measles or mumps needing a 3^rd dose of measles-mumps-rubella vaccine (MMR3). But we don’t know how accurate routine blood tests are or how well MMR3 protects young adults. In this study, we sent blood to a specialised reference laboratory in the Netherlands for more sensitive antibody tests, not available in New Zealand, before and after MMR3. Of 45 students with measles antibody below the Dunedin cut-off, only 8 (17.4%) were also low on the more sensitive reference test – but even this test missed 3/10 low results compared with a third “best in show” test. Importantly, no student who was low on more sensitive tests was missed by the cut-offs used in Dunedin. After receiving MMR3, 32 (94%) had antibody levels above the Dunedin cut-off and the other two were above the cut-off on the specialised Netherlands assay. All mumps negatives responded strongly. Conclusion: Although not as sensitive as more specialised tests, testing at Otago identified all students needing MMR3 and antibody responses to measles and mumps post MMR3 were very good.

ADEPT-MACTODD Charitable Trust

Researchers: Professor John Reynolds, Dr Mariana Leriche Vasquez, Dr Ben Brockway, Dr Nich Cutfield
Project Title: Detecting changes in habits in rapid eye movement sleep behaviour disorder (RBD): a pilot study
Lay Abstract: One of the early signs of Parkinson’s disease (PD) is the loss of habitual movements, however it is unclear if this loss is also present in disorders associated with PD. We have developed a simple computational tool by which to detect habit loss and will test a sample of people with a condition called rapid eye movement sleep behaviour disorder (RBD). Comparison between results obtained from RBD and healthy participants with our ongoing PD study, will allow us to determine the specificity of our tool for PD and the ability to detect habit loss in a population with some association with PD.

Mike Bird and Friends of the Foundation

Researchers: Professor Alison Heather (Physiology) & Dr Louise Bremer (SDHB)
Project Title:  Serum estrogen receptor bioactivity and breast cancer risk
Lay Abstract: Breast cancer is the most frequently diagnosed cancer in women. All women are at risk of recurrence after mastectomy. The measurement of serum estradiol in these patients can be used to guide therapy and as a prognostic tool. Unfortunately, estradiol measurements have proven unreliable on both counts. In contrast, estrogen receptor bioactivity is reported to be high in women that develop breast cancer. As such, there is now considerable interest in using estrogen receptor bioassays to track breast cancer patients. We aim to measure estradiol levels and estrogen receptor bioactivity in serum of women pre and post-aromatase inhibitor treatment. If the bioassay identifies estrogen receptor bioactivity beyond that derived from residual estradiol levels, this will provide a major impetus for discovering non-classical estrogens that can drive recurrence.

OceanaGold

Researchers: Dr. Htin Lin Aung & Thomas Devine (Microbiology & Immunology)
Project Title: Transcriptional Profiling of the New Zealand Tuberculosis Rangipo strain within macrophages
Lay Abstract: Tuberculosis (TB) is the number one cause of death from an infectious disease in the world. Elevated TB rates among indigenous peoples are a major theme in the history of worldwide TB. Despite New Zealand being a low TB burden country, the disease has a disproportionately higher incidence in Maori (six times higher) when compared to New Zealand Europeans and the causes of the disparity in TB infection between Maori and Non- Maori remain unknown. TB is a prime example of a "social disease" with the risk factors including a complex combination of human factors (obesity, diabetes, smoking and alcohol use), socio-economic factors (crowding, poverty and unemployment) and bacterial factors (strain and transmissibility). In addition, a New Zealand unique Mycobacterium tuberculosis (MTS) strain known as the Rangipo strain is highly prevalent in Maori. In this study, we will unravel the genetics of the Rangipo strain to discover its transmission characteristics compared to other strains in the Maori population. 

JN Lemon Charitable Trust

Researchers: Dr Roslyn Kemp, Paulo Urbano, (Microbiology & Immunology) & Prof Michael Schultz (Medicine)
Project Title: The control of inflammation by regulatory T cells - an immune- intestinal organoid model
Lay Abstract: Inflammatory bowel diseases (IBD) are caused by uncontrolled inflammation in the gut. This inflammation causes a breakdown in gut function, chronic pain and inflammation. Many factors are involved in both the cause and progression of IBD, including the immune system, the gut microbiome, the epithelial barrier, and the genetic background of the individual. The immune response is usually controlled by a type of immune cell, regulatory T cells (Tregs) to prevent inflammation. We plan to study the types of Tregs in people with IBD using intestinal organoids, which replicate the epithelial barrier, immune response and gut microbes from individual patients.

The Southern Trust

Researchers: Assoc Prof Joanna Kirman & Dr James Ussher (Microbiology & Immunology)
Project Title: Improving vaccination against TB: inducing trained innate immune cells in the lungs
Lay Abstract: Tuberculosis (TB) kills more people annually than any other single infectious agent. The existing vaccine, BCG, protects children but not adults against TB. Understanding the protective immune mechanisms of the BCG vaccine is a critical first step to progress development of an improved TB vaccine that will also protect adults. This study will investigate a new idea - that the first responding immune cells (innate cells) can be trained by vaccination. We will provide the first insight into whether innate immune training is uniform across lung innate cells following BCG vaccination or whether certain innate cells are more "trainable" than others.

Margaret Begg Charitable Trust

Researchers: Dr. Narun Pornpattananangkul (Psychology), Dr. Argyris Stringaris (NIH, USA)
Project Title: Motivation and Cognitive Abilities as Mediators between Polygenic Scores and Psychopathology in Children

Lay Abstract:The role that genes play in increasing the risk for mental disorders such as major depressive disorder (MDD) and attention deficit hyperactivity disorder (ADHD) becomes increasingly clear. Yet, we still don’t know what psychological and cognitive links between genetic risk and psychiatric symptoms are. Here we focus on three such links, namely:  

1) how sensitive children are to negative/aversive situations;

2) how sensitive children are to positive/motivational situations; and

3) how well children are in performing cognitive-demanding tasks in general.

We found that the influences of MDD and ADHD genetic liability on psychopathology were partly explained by these three psychological and cognitive mechanisms. Accordingly, these findings suggest targets for potential preventions and interventions for children with genetic liability.

Otago Community Trust

Researchers: Dr Louise Bicknell & Dr Karen Knapp (Pathology)
Project Title: Investigating the mechanisms of a novel genetic cause of intellectual disability
Lay Abstract: We have identified genetic alterations in 20 patients with intellectual disability in novel disease genes that serve to fit DNA inside cells. While our genetic evidence is significant, we need to understand how these alterations impact the normal functioning of the encoded protein. In particular, the association of these proteins with DNA is dynamic, and we hypothesize the efficiency of this dynamic association could be impacted by these genetic alterations, ultimately impacting normal cell functioning during brain development. Our research has the potential to gain insight into more common, complex neurodevelopmental conditions such as autism, epilepsy and developmental delay.

Otago Community Trust

Researchers: Professor Mike Eccles, Dr Aniruddha Chatterjee, Dr Euan Rodgers (Pathology), Dr Chris Jackson (SDHB)
Project Title: A blood-test to epigenomically predict melanoma patient response to lmmunotherapy
Lay Abstract: These are exciting times for cancer immunotherapy, since after many frustrating years, immunotherapies using Keytruda, Opdivo and similar drugs have now become clinically validated and successful treatments for a number of cancer types. However, only a small proportion of treated patients actually respond to these treatments, while all treated patients frequently are susceptible to permanent and debilitating adverse drug effects. Unfortunately, no accurate predictive tests are available at present for determining who will respond to treatment. In this project we will identify markers from blood to eventually allow us to develop a convenient blood-test to predict melanoma patient response to immunotherapy.

 

OceanaGold

Prof Iain Lamont & Dr Kay Ramsay (Biochemistry)
The effect of sub-lethal concentrations of antibiotics on Pseudomonas aeruginosa.

The bacterium Pseudomonas aeruginosa causes severe respiratory infection for individuals with cystic fibrosis (CF). Regular and prolonged antibiotic treatment is required to maintain patients’ health. During periods of treatment P. aeruginosa within the airways are often exposed to sub-lethal amounts of antibiotics. Limited studies have shown that an increase in antibiotic resistance of P. aeruginosa can occur under these conditions, but have not examined bacteria from CF individuals or investigated the mechanisms of resistance. By exposing clinical and laboratory strains to sub-lethal amounts of clinically relevant antibiotics over an extended period we have shown that this exposure is sufficient to alter the effectiveness of antibiotic treatment. This is reflected in detrimental changes seen within the DNA of these bacterium. Understanding the genetic basis of resistance has potential for improved use of antibiotics, by using DNA testing to guide prescription. Results from this research will contribute to the knowledge of P. aeruginosa resistance, influence therapeutic choices and ultimately has potential to better the clinical outcome for patients. 

Our study has shown that bacteria can develop antibiotic resistance when exposed to sub-lethal amounts of antibiotic. This finding helps to explain the emergence of antibiotic-resistant bacteria during chronic infections such as in cystic fibrosis.  

JN Lemon Charitable Trust

Dr Shyamal Das (Pharmacy), A/Prof Rajesh Katare (Physiology), Prof Phillip Hill (Preventive and Social Medicine), Dr Jack Dummer (Medicine)
Evaluation of safety and pharmacokinetics of inhaled rifampicin in rats.
Tuberculosis (TB) is an infectious disease primarily localized in the lung although it can affect other organs. Current oral and parenteral treatment using high doses of multiple drugs is ineffective since only small fraction of drug goes to the lung. Potentially more effective treatment can be achieved by pulmonary delivery of anti-TB drugs ensuring high levels of drugs in both lungs and blood. This is a pre-clinical study of inhaled rifampicin, a first line anti-TB drug, powder in rats to evaluate its safety and pharmacokinetics. This will enable design of clinical studies on inhaled rifampicin and other anti-TB drugs

Southern Victorian Charitable Trust

Dr Lyn Wise & Prof Michelle Glass(Pharmacology  and Toxicology (Psychological Medicine)
Refining vascular networks through biased receptor tyrosine kinase signaling.
Tyrosine kinase receptors are critical to the development and regeneration of any tissue in our body. Aberrant expression of these receptors has been linked to a diverse range of disorders from growth and healing defects, to pathological inflammation and cancer. This research aims to discover the mechanism behind signalling bias in these receptors. This will be the first step towards development of drugs that refine vascular networks, with the ramifications extending from the engineering of vascularised bone or skin, to therapeutic angiogenesis for ischaemic tissues, to the normalisation of retinal or tumour vasculature.

Mike Bird and Friends of the Foundation

Dr Luke Wilson (Medicine), Prof Dirk de Ridder & Dr Sook Ling Leong (Surgical Sciences)
Closed-loop neurofeedback on the cardiac autonomic nervous system, a pilot study.
Alterations in the nervous control of the cardiovascular system is an independent risk factor for cardiovascular disease and is difficult to treat. We will use a brain training technique known as lnfraslow neurofeedback for two key areas of the brain that are known to positively impact the nervous control of the cardiovascular system in healthy individuals. If the findings of the infraslow neurofeedback training are positive we will attempt this form of training in patients with known alterations in the nervous control of the cardiovascular system

OTAGO COMMUNITY TRUST

Dr Kiel Hards & Prof Greg Cook (Microbiology and Immunology)
How do proton-motive forces correlate with antimicrobial efficacy?
Antimicrobials were once the “one-size fits all” approach to varied societal problems; such as controlling infections in human, animals and plants, or their extensive use as growth promoters in food animals. However, microorganisms appear to be winning the drug arms race and, without more dedicated research, they threaten to return society to a pre-antibiotic era. It’s known that all organisms produce a kind of biological electricity, usually a proton­ motive force (PMF), when they respire. Recently, it was found that short-circuiting this electricity is an incredibly effective property in antimicrobials. Our research proposes to investigate how new drugs affect the PMF in various human pathogens, focusing on the Tuberculosis bacterium.

Dr Nicholas Fleming (Pathology), Dr Peter Shepherd (Auckland University), Prof John McCall (Surgical Sciences)

A new biomarker for colorectal cancer prognosis and targeted therapy in southern New Zealand. Otago, Southland and South Canterbury have the highest rates of death due to bowel cancer in New Zealand, being approximately 25% higher than the national average. We have analysed 192 patients from these districts and identified a common and easily testable genetic feature that indicates who will get earlier and faster progressing bowel cancers. The feature has immediate value for predicting the course of the disease in southern New Zealand, but may have greater value for indicating which therapies are most likely to work, including immunotherapy. The work has now been expanded in scope due to co-funding by the HRC, and we have explored the cellular mechanisms that likely contribute to the effects of the feature. The feature may guide the successful use of this drug for bowel cancer patients in southern New Zealand.

Mike Bird and Friends

Engineering yeast as an ideal expression host for human P-glycoprotein (ABCB1)
Dr Erwin Lamping & Dr Nicholas Heng (Department of Oral Sciences, School of Dentistry, University of Otago) & Prof Richard Cannon (Sir John Walsh Research Institute, School of Dentistry, University of Otago)
P-glycoprotein (P-gp) is a very important human membrane protein. It pumps toxic compounds out of cells, but it also causes tumours to become resistant to anti-cancer drugs. Thus, we need to find inhibitors of P­gp in tumours but not in healthy cells. We plan to study P-gp in our baker’s yeast model which have other membrane protein pumps removed. This study aims to discover how we can get high levels of functional P-gp in yeast and measure the interaction of drugs with P-gp. The results of this research will be important for discovering alternative routes to treating cancer and other diseases.

OceanaGold

Understanding the role of the brain in the onset of menopause
Dr Xinhuai Liu & Professor Allan Herbison (Department of Physiology, School of Biomedical Sciences, University of Otago)
With the continuing increase in life-span, more and more women live with menopause. Menopause women are more prone to develop diseases such as cardiovascular disease and osteoporosis. To optimize the long-term well-being of midlife women, it is necessary to elucidate mechanisms underlying the onset of menopause. In this project, we will use a mouse model to identify changes in the brain following induction of menopause and endocrine alterations.

JN Lemon Charitable Trust

Resistance is futile: Investigating collateral hypersensitivity to combat antibiotic resistance
Dr Wayne Patrick (Department of Biochemistry, School of Biomedical Sciences, University of Otago)
This is a war, and one that humankind is losing. Microbes have now evolved mechanisms of resistance to every available class of antibiotic. Rather than focusing on the costly development of new antibiotics, this work will investigate an alternative strategy that manipulates an aspect of bacterial evolution known as collateral hypersensitivity. Evolving resistance to one antibiotic often results in increased sensitivity to others. Currently, a detailed understanding of this phenomenon does not exist. We will use high­ throughput approaches to systematically map the collateral hypersensitivity profiles of three resistant bacterial species. Ultimately, this may allow doctors to prescribe exactly the right antibiotic, every time.

Southern Victorian Charitable Trust

Can microRNA be used as a biomarker to predict treatment response in anxiety?
Associate Professor Bruce Russell (School of Pharmacy, University of Otago), Dr Margaret Ryan (Department of Anatomy, School of Biomedical Sciences, University of Otago) & Professor Paul Glue (Department of Psychological Medicine, Dunedin School of Medicine, University of Otago)
Most medical conditions such as hypertension have an easily measureable target such as blood pressure that can be used to diagnose and measure treatment success; however, mental illnesses do not. This is mostly due to the complexity of the human brain. This project aims to find a small compound in the blood that can used to diagnose and then predict whether or not someone with severe anxiety will respond to treatment.

Novel insights into the genetics of osteoporosis through studying the genome of a NZ family

Dr Louise Bicknell & Dr Karen Knapp (Department of Pathology, Dunedin School of Medicine, University of Otago)
Osteoporosis is a chronic skeletal disease associated with decreased bone mineral density and structural deterioration of bone architecture, affecting more than 80,000 people in New Zealand and over 200 million people worldwide. Our current understanding of the genetic causes of osteoporosis is incomplete and a better understanding of bone physiology is essential to facilitate the ongoing search for improved therapeutics for osteoporosis. We have a unique opportunity for the discovery of both novel candidate genes and new mechanisms regulating bone remodelling in osteoporosis, through studying a New Zealand family in which a boy is severely affected by syndromic juvenile osteoporosis. Through studying the genome of this New Zealand family, we have the potential to discover novel insights into the genetics of osteoporosis.

Infraslow neurofeedback for food craving in overweight and obese women, a pilot study

Professor Dirk de Ridder & Dr Sook Ling Leong (Department of Surgical Sciences, Dunedin School of Medicine, University of Otago) & Associate Professor Patrick Manning (Department of Medicine, Dunedin School of Medicine, University of Otago)
There are several areas in the brain related to reward processing that encourage overeating. Brain imaging studies have shown that certain patterns of brain activity seen in overweight and obese individuals are similar to those shown in addiction. One implicated area is called the posterior cingulate cortex (PCC), which appears to function abnormally in individuals who are addicted to food. lnfraslow neurofeedback, which utilises real time display of brain activity to allow self-regulation of brain function, may help reduce food craving in people with signs of food addiction who have abnormalities in the PCC.

Bioenergetics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Professor Warren Tate (Department of Biochemistry, School of Biomedical Sciences, University of Otago) & Dr Lynette Hodges (School of Sport and Exercise, Massey University)
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a severely debilitating unexplained illness that has a distinguishing symptom of exercise intolerance or “post-exertional malaise”. We aim to focus on this feature of the illness by addressing bioenergetic functions of the cell’s energy powerhouses, the mitochondria, in ME/CFS patients compared to healthy controls. Literature has suggested that ME/CFS patients have significantly low levels of Co-enzyme Q 10 (CoQ) and we aim to determine whether the commercial supplement MitoQ10 (developed in 2001 at the University of Otago) that targets CoQ to the mitochondria will improve energy producing functions in cells from ME/CFS patients.

Immune cells in the stroke microenvironment – Drivers of differential outcomes in obesity?

Associate Professor Sarah Young & Dr Silke Neumann (Department of Pathology, Dunedin School of Medicine, University of Otago) & Dr Andrew Clarkson (Department of Anatomy, School of Biomedical Sciences, University of Otago)Stroke is one of the leading causes of death and long-term disability in New Zealand, with limited treatment  options available. Inflammation of affected brain regions is a major complication of stroke and strongly impairs nerve cell repair and rehabilitation. Underlying medical conditions, such as obesity and diabetes dramatically increase the likelihood of experiencing a stroke and further impede the healing process. In this project, we aim to understand the role of immune cells that drive inflammation after a stroke  and how these contribute to worse outcomes in obese and diabetic patients.

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.

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.

Southern Victorian Charitable Trust

Can microRNA be used as a biomarker to predict treatment response in anxiety?
Associate Professor Bruce Russell (School of Pharmacy, University of Otago), Dr Margaret Ryan (Department of Anatomy, School of Biomedical Sciences, University of Otago) & Professor Paul Glue (Department of Psychological Medicine, Dunedin School of Medicine, University of Otago)
Most medical conditions such as hypertension have an easily measureable target such as blood pressure that can be used to diagnose and measure treatment success; however, mental illnesses do not. This is mostly due to the complexity of the human brain. This project aims to find a small compound in the blood that can used to diagnose and then predict whether or not someone with severe anxiety will respond to treatment.

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.

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).

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.
$19,986 (Oceanagold)
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.

Professor Alison Heather

Physiology: Defining estradiol’s bad effects on atherosclerosis: targeting safe HRT for women.
$25,000
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.
$30,000
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.

Associate Professor Alex Mclellan

Microbiology & Immunology: Understanding how cancer spreads to the lymph nodes.
$29,006
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?
$33,470
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.
$33,881
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.
$13,500
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.

Professor Cliff Abraham & Dr Joanna Williams

Psychology & Anatomy: Defining the novel contribution of microRNA to long-term memory mechanisms.
$20,000
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.
$23,000
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.
$25,687
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.

Dr Anita Dunbier

Biochemistry: Investigation of genes involved in breast cancer susceptibility and response to therapy.
$12,532
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?
$30,150
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.
$24,000

Dr Adele Woolley & Professor Anthony Braithwaite

Pathology: Putting a novel prognostic marker for breast cancer through its paces.
$30,000
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
$25,000
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.

Assistant Prof Grant Butt

Physiology: Colonic sodium bicarbonate and inflammatory bowel disease.
$30,000
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.
$25,449
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.