Thursday 6 June 2013 10:16am
Professor Richard Blaikie
Deputy Vice-Chancellor (Research & Enterprise)
Otago researchers have gained around $15.5m in Health Research Council (HRC) funding to undertake a range of innovative projects aimed at improving the health and wellbeing of New Zealanders.
The 10 Otago contracts in the annual funding round announced today include a major five-year programme investigating how proteins from a virus usually found in sheep can be exploited to provide potential therapies for skin wounds and other conditions in humans, such as cancer, inflammatory disorders and viral infection.
Professor Andrew Mercer of the Department of Microbiology and Immunology will lead this $4.9m programme, which follows on from his and colleagues’ discovery that orf virus expresses an astonishing array of novel proteins that allow it to cause severe skin lesions that, remarkably, heal without scarring.
Researchers from across the University’s Dunedin, Christchurch and Wellington campuses have also gained funding for nine other world-class projects. These range from gaining important insights into cancer genetics, to developing and assessing a school-based asthma support toolkit for Māori children, who are twice as likely to be hospitalised by the condition.
Deputy Vice-Chancellor (Research and Enterprise) Professor Richard Blaikie welcomed this significant support from the HRC and congratulated all the recipients on their successes in what is a highly contested funding round.
“This is an endorsement of the calibre of work undertaken by Otago’s researchers and a vote of confidence in their ability to generate significant research outcomes that promise to advance our health and wellbeing,” Professor Blaikie says.
Among the Otago projects are investigations into a protein variant that may hold the key to the invasiveness and spread of cancer, screening for new classes of antifungal drugs to overcome increasing resistance problems, and evaluating a promising new surgical technique for treating a common form of heart failure that currently has no effective treatment.
Two biomedical projects focus on a recently discovered molecule called kisspeptin, which plays a central role in the brain’s master control of fertility and reproduction. The projects will delve into its potential role in normal and problem pregnancies, and in female and male infertility caused by excessive levels of the hormone prolactin, respectively.
Developing methods to predict how well individual rheumatoid arthritis patients will respond to expensive drug treatments is the goal of project, which involves profiling patients’ genetic variations along with inflammatory markers in their blood.
One clinical research project aims to identify the best way to manage the care of young women with cervical abnormalities called CIN2, which can progress to cancer but often regress spontaneously.
Another project will examine why pregnant Māori women, or those who have recently delivered, may be at increased risk of severe acute maternal morbidity (SAMM), whether the severity of disease is preventable, and what impact any disproportionate burden of harm has on Māori women, their whānau and the health service.
For more information, contact
Professor Richard Blaikie
Deputy Vice-Chancellor (Research & Enterprise)
University of Otago
Tel 64 3 479 8513
Email dvc.research@otago.ac.nz
Otago’s new HRC contracts
Please note, only the first named investigator is listed.
Programme:
Professor Andrew Mercer (Microbiology and Immunology)
Exploiting the therapeutic potential of viruses
60 months, $4,937,329
Telephone: 03 479 7730
Projects:
Professor Antony Braithwaite (Pathology)
Does the D133p53 isoform promote cancer invasion and metastasis?
36 months, $1,185,648
Telephone: 03 479 7165
Associate Professor Colin Brown (Physiology)
Central regulation of natural birth processes
36 months, $1,003,783
Telephone: 03 479 7354
Professor David Grattan (Anatomy)
Role of kisspeptin in hyperprolactinemia-induced infertility
36 months, $1,164,184
Telephone: 03 479 7442
Mrs Bernadette Jones (Medicine, Wellington)
He kura: asthma support for Maori tamariki at school
36 months, $1,199,064
Telephone: 04 918 6845
Associate Professor Beverley Lawton (Primary Health Care and General Practice, Wellington)
With co-funding from the Ministry of Health
Addressing the burden and preventability of severe acute maternal morbidity
36 Months, $1,199,906
Telephone: 04 806 1893
Dr Brian Monk (Oral Sciences)
Structure-directed antifungal discovery
36 months, $1,190,954
Telephone: 03 479 7099
Professor Mark Richards (Medicine, Christchurch)
Renal denervation in heart failure with preserved ejection fraction
36 months, $1,195,997
Telephone: 03 364 1117
Professor Lisa Stamp (Medicine, Christchurch)
Predicting response to anti-TNF therapy based on serum cytokine and gene profile
36 months, $1,199,969
Telephone: 03 364 0953
Associate Professor Peter Sykes (Obstetrics and Gynaecology, Christchurch)
The conservative management of young women with CIN2
48 months, $1,196,179
Telephone: 03 364 4647
Professor Andrew Mercer (Microbiology and Immunology)
Exploiting the therapeutic potential of viruses
Unravelling the complex interactions between viruses and humans reveals sophisticated viral replication strategies but, importantly, it also gives unique insights into our own physiology and immune defences. Furthermore, and rather paradoxically, viruses are proving to be an exciting source of new therapeutics for the treatment of a wide range of human diseases. The large complex poxvirus, orf virus, causes severe skin lesions that, remarkably, heal without scarring. Our studies have revealed that this virus expresses an astonishing array of novel proteins that may explain this phenomenon. Some of these viral proteins are secreted from infected cells and dampen inflammation or increase blood supply to infected tissue, while others work within infected cells to protect the virus from our defences. Our goal is to develop these orf viral proteins as new therapeutics for the treatment of acute and chronic human conditions including skin wounds, cancer, inflammatory disorders and chronic viral infection.
In further projects within our Programme we will examine the therapeutic potential of other viral proteins we have discovered. We will (1) determine if a novel viral regulator of cell replication has anti-cancer therapeutic potential; (2) explore the links between a family of viral proteins and pathways regulating cellular responses to low oxygen such as occurs in tumours; (3) characterise new mechanisms by which viruses counteract our antiviral responses.
Other named investigators from Otago involved in the Programme are Dr Stephen Fleming (Microbiology and Immunology); Dr Lyn Wise (Microbiology and Immunology); Professor Kurt Krause (Biochemistry); Dr Torsten Kleffman (Biochemistry); and Dr Merilyn Hibma (Microbiology and Immunology). Dr Wise will lead Project A: “Viral factors as novel therapeutics for human skin wounds” Professor Mercer leads Projects B and C: “Characterisation and exploitation of a novel cell cycle regulator” and “Functional analysis of OV ankyrin repeat (ANK) proteins” while Dr Fleming will lead Project D: “How does OV counteract host cell antiviral responses?”
Professor Mercer is a member of the Webster Centre for Infectious Diseases and Genetics Otago, which are both formally designated University of Otago Research Centres.
Professor Antony Braithwaite (Pathology)
Does the D133p53 isoform promote cancer invasion and metastasis?
This proposal addresses the hypothesis that human Δ133p53 protein variant promotes tumour invasion and metastasis (tumour spread) via inflammation, and as such is a key contributor to cancer mortality. We will address this in part using a genetically modified mouse we generated that makes a protein (Δ122p53) similar to human Δ133p53. This is the only available mouse model of Δ133p53. We will examine Δ122p53 mice in detail for evidence of metastasis and angiogenesis (development of a tumour blood supply). In parallel, based on leads from analysis of Δ122p53 mice and gene analysis of human tumours, we will investigate whether Δ122p53 promotes invasion in cell culture and regulates the activity of the pro-inflammatory gene, IL-6, known to promote metastasis. We will analyse human cancers to investigate a relationship between Δ133p53 levels, inflammatory gene activities and tumour metastasis. As patients die of metastasis, understanding this process provides the best option for intervention.
The other named investigator from Otago in this project is Emeritus Professor Margaret Baird.
Associate Professor Colin Brown (Physiology)
Central regulation of natural birth processes
The aim of this project is to understand the fundamental biological processes that control pregnancy. Problem pregnancies, particularly preterm delivery, risk death for the baby, and those babies who survive are more likely to suffer chronic illness as adults. The hormone, oxytocin, is secreted from the brain to contract the uterus for delivery of the baby. Inappropriate oxytocin secretion contributes to problem pregnancies, including preterm delivery. We have discovered that central administration of a newly-identified neuropeptide, kisspeptin, excites oxytocin-secreting cells only in late pregnancy. However, the impact of this excitation on pregnancy remains to be determined. We will genetically manipulate kisspeptin receptors on oxytocin cells in mice to determine whether central kisspeptin excitation of oxytocin cells is required for successful delivery. This work will increase our knowledge of the biological processes required for normal pregnancy and underpin the development of alternative strategies to manage problem pregnancies.
Other named investigators from Otago involved in this project are Dr Victoria Scott (Physiology) and Mr Gregory Bouwer (Physiology).
Associate Professor Brown is a member of the Centre for Neuroendocrinology, a formally designated University of Otago Research Centre.
Professor David Grattan (Anatomy)
Role of kisspeptin in hyperprolactinemia-induced infertility
One in six couples will face infertility. Excessively high prolactin in the blood is a major cause of infertility in both males and females. The mechanism by which prolactin affects fertility is not fully understood, but it involves an inhibitory action on the hypothalamic neurons controlling reproduction (GnRH neurons). We have shown that GnRH neurons do not have prolactin receptors, hence prolactin must be indirectly regulating these neurons through other prolactin-sensitive pathways. We have recently identified that kisspeptin neurons, a key neuronal pathway regulating GnRH neurons, express prolactin receptors. Using state-of-the art transgenic approaches that are unique to our laboratory, we are in a position to critically test the hypothesis that prolactin regulation of kisspeptin neurons is required for infertility induced by hyperprolactinemia. These studies will help develop better treatments for infertility, and may provide opportunity for the development of novel contraceptives.
The other named investigator from Otago in this project is Dr Rosemary Brown (Anatomy).
Professor Grattan is a member of the Centre for Neuroendocrinology, a formally designated University of Otago Research Centre.
Mrs Bernadette Jones (Medicine, Wellington)
He Kura: Asthma Support for Maori Tamariki at School
Asthma is the most common chronic childhood disease affecting up to one in four NZ children. Significant ethnic disparities exist for Māori in asthma related illness, with Māori children twice as likely to be hospitalised as non-Māori. The ways in which schools support a child with asthma can have a significant impact on their overall asthma control and affect the child’s ability to learn. Strategies to improve asthma management in NZ schools have not been investigated and no national policy exists to guide schools. Under a Kaupapa Māori methodology, and in partnership with Māori community providers and governmental agencies, we will assess a Māori-centred, school-based asthma intervention to improve outcomes for children with asthma. This will result in the development of an evidence-based, asthma toolkit for primary schools which will reduce asthma disparities, inform health-in-education policy, and act as a template for the management of other chronic conditions in schools.
Other named investigators from Otago involved in this project are Dr Tristam Ingham (Medicine, Wellington), Ms Bridget Robson (Public Health, Wellington) and Mr Gordon Purdie (Public Health, Wellington)
Associate Professor Beverley Lawton (Primary Health Care and General Practice, Wellington)
Addressing the burden and preventability of severe acute maternal morbidity
Pregnant Māori women and their children are more likely to suffer harm and death than non-Māori women. Severe acute maternal morbidity (SAMM) occurs in more than 1% of all pregnant women and is associated with considerable personal and public health care costs. Our previous research suggests that Māori women may be at increased risk of preventable SAMM. The proposed study will examine the reasons why some pregnant women become severely ill, whether the severity of disease is preventable, and what impact any disproportionate burden of harm has on Māori women, their whānau, and the health service. This work will highlight the importance of keeping women at risk of a SAMM event from progressing along the continuum of morbidity. The overall goal of this proposal is to study causes and consequences of preventable severe acute maternal morbidities to reduce the impact of severe harm for pregnant Māori women and their whānau.
Other named investigators from Otago involved in this project include Dr Evelyn Macdonald, Ms Selina Brown, Ms Susan Garrett (all Primary Health Care and General Practice, Wellington), Ms Bridget Robson (Public Health, Wellington), Dr James Stanley (Dean’s Department, Wellington), and Dr Sara Filoche (Primary Health Care and General Practice, Wellington)
Dr Brian Monk (Oral Sciences)
Structure-directed antifungal discovery
There is an urgent need to augment the widely-used and well-tolerated but drug resistance-susceptible triazole drugs with broad-spectrum antifungals that target fungal lanosterol 14α-demethylase (Erg11p) and not human CYP51. We have obtained high-resolution X-ray crystal structures of yeast Erg11p with substrates and triazole inhibitors bound. We will apply our unique knowledge of cytochrome P450 structure and function and use a comprehensive set of screens to identify new antifungals.
Our research will confirm key biochemical properties of the enzyme, identify a product egress pathway, and resolve the structures of the Erg11ps of several important fungal pathogens and human CYP51. Computer aided drug design, yeast-based high throughput screens, secondary screens, counterscreens plus a combinatorial chemistry capacity will be used to identify efficiently optimal hits as Erg11p-specific drug candidates. The identification of new classes of antifungals will provide models for drug discovery and development that circumvent the ubiquitous activities of cytochrome P450 enzymes.
Other named investigators from Otago involved in this project are Professor Richard Cannon (Oral Sciences), Dr Joey Tyndall (School of Pharmacy), and Dr Mikhail Keniya (Sir John Walsh Research Institute).
Dr Monk is a member of the Sir John Walsh Research Institute, a formally designated University of Otago Research Centre.
Professor Mark Richards (Medicine, Christchurch)
Renal denervation in heart failure with preserved ejection fraction
We will test a new approach to a form of heart failure (HF) with no current treatment proven to reduce death rates or hospitalisations. Over a third of HF cases have preserved ejection fraction (HFPEF) often on a background of high blood pressure (BP). These "stiff" hearts pump strongly but fill inefficiently resulting in poor exercise capacity and high death rates. Treatments that help when heart pumping action is poor are of no benefit in HFPEF. Recently a simple catheter procedure removing excess nerve signals to and from the kidneys ("renal denervation"; RON) has been able to reduce BP in patients with high BP resistant to multi-drug treatment. Through removing excess nervous drive to the kidneys, heart and circulation this treatment has promise in HF. We will compare effects of RON and standard medical treatment on heart function, exercise capacity and quality of life in 144 patients with HFPEF.
Other named investigators from Otago involved in this project are Associate Professor Richard Troughton Dr James Blake and Associate Professor Christopher Frampton (all of the Department of Medicine, Christchurch).
Professor Richards is Director of the Christchurch Heart Institute, a formally designated University of Otago Research Centre.
Professor Lisa Stamp (Medicine, Christchurch)
Predicting response to anti-TNF therapy based on serum cytokine and gene profile
The introduction of "biological" disease modifying anti-rheumatic drugs (bDMARDs) has been a major advance in the treatment of rheumatoid arthritis (RA). When conventional therapy fails, bDMARD therapy can be life changing. bDMARDs specifically target key components in the pathways of inflammation causing RA, such as the pro-inflammatory cytokine tumour necrosis factor-a (TNF). Consequently, knowledge of the inflammatory pathways active in individual patients is required for efficient targeting of bDMARDs. We have established a classification of joint synovial tissues, based on the expression of interleukin (IL) 17-A and CD21L genes, reflecting different inflammatory states. Our objective is to determine if we can predict response to anti-TNF therapy based on this system and concentrations of IL-17-related cytokines. The ability to predict response to treatment will improve outcomes for patients with RA and provide cost savings by ensuring that those patients most likely to respond receive these highly effective but expensive drugs.
Other named investigators from Otago involved in this project are Dr Paul Hessian (Medicine, Dunedin) and Professor John Highton (Medicine, Dunedin).
Professor Stamp is a member of the Arthritis Research Theme, a formally recognised Research Theme of the University.
Associate Professor Peter Sykes (Obstetrics and Gynaecology, Christchurch)
The conservative management of young women with CIN2
By completing this research we wish to identify whether we can safely reduce treatment related complications, for young women with moderate screen detected abnormalities of the cervix {CIN2). Evidence suggests that a significant proportion of abnormalities will regress spontaneously and therefore treatment for all such lesions is unnecessary. There is evidence that in addition to immediate complications, cervical treatments can have an adverse effect on pregnancy outcomes. Despite screening program recommendations of immediate treatment, many colposcopists consider that these young women should be offered observation as an alternative to immediate treatment. There is however insufficient data on which to base routine practice. We are performing a large multicenter study that will describe the safety and outcome of an observational approach; it will also identify factors that predict regression. This will allow an evidence-based approach to management decisions and screening program recommendations for women under 25 with CIN2.
Other named investigators from Otago involved in this project are Dr Bryony Simcock (Obstetrics and Gynaecology, Christchurch), Dr Merilyn Hibma (Microbiology and Immunology), and Associate Professor Beverley Lawton (Primary Health Care and General Practice, Wellington)
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