2016 Funded Projects
Intravenous Vitamin C and severe sepsis outcomes - randomised controlled trial
Dr Anitra Carr, University of Otago.
Sepsis and septic shock are caused by a systemic inflammatory response to severe infection that results in multiorgan failure and refractory hypotension. The incidence of severe sepsis is increasing and is the leading cause of mortality in critically ill patients. Preliminary data indicates that sepsis results in significant depletion of vitamin C levels and a recent Phase I study demonstrated that administration of vitamin C to patients with severe sepsis dramatically improved inflammatory biomarker levels and clinical outcome measures. Vitamin C acts as a cofactor for numerous regulatory and biosynthetic enzymes, including those responsible for vasopressor synthesis. Therefore, we hypothesise that vitamin C administration will improve sepsis-related disorders such as hypotension through its enzyme cofactor activities. This Phase II randomised controlled trial will assess the effects of vitamin C infusion on hypotension and vasopressor requirements, as well as markers of oxidative stress, inflammation and leukocyte activity, in patients with severe sepsis. The biochemical mechanisms of action will be determined by measuring a suite of clinically-relevant and novel cofactor activity biomarkers. Overall, this study will establish the efficacy of vitamin C in improving clinical outcomes in the critically ill.
Contribution of enterotoxigenic Bacteroides fragilis to colorectal carcinogenesis
Dr Rachel Purcell, University of Otago
Colorectal cancer is a common type of cancer, and while recent evidence suggests that gut bacteria may increase risk, the exact mechanisms remain elusive. Bacterial infections can cause chronic inflammation, which has been linked to cancer development. The Bacteroides fragilis toxin potentially alters intracellular signalling pathways that are also linked to cancer development. We will explore how chronic inflammation as a result of enterotoxigenic B. fragilis (ETBF) infection is associated with development of colorectal cancers, including whether genetic mutations arise as a result of this chronic inflammation. We will also investigate the role of microRNAs as a potential mechanism that regulates this process. MicroRNAs are small RNA molecules that do not code for proteins, but have recently been shown to play important roles in many cellular processes, including the development of cancer. We hope that this project will identify novel markers for the early detection of colorectal cancer.
Measurement of Mitochondrial Function during Human Ageing
Dr Andree Pearson, University of Otago
Human life expectancy has increased considerably in the last century, but along with this advance has come the increased burden of age-related disease and disability. Interventions that promote healthy ageing are limited, and new advances will depend on improved understanding and measurement of the underlying biological processes. Mitochondria are the site in our cells where food is converted into energy. Mitochondrial dysfunction isclosely linked to ageing, however there is an absence of non-invasive methods for measuring mitochondrial function in humans. We will attempt to use new technology to measure the health of mitochondria in cells isolated from a small blood sample. We will compare mitochondrial function in an elderly population with that of a younger population, and also examine how effectively the antioxidant defences of ageing mitochondria cope with an oxidative stress. This project will provide insight into the biological processes underlying human ageing, and methodology to measure these processes in the general population.
Pilot Study of Cognitively-Enhanced Interpersonal and Social Rhythms Therapy for Depression
Dr Katie Douglas, University of Otago
Major depressive disorder (MDD) involves significant morbidity, suicide risk, and recurrent hospitalisations. After recovery from a depressive episode, individuals often continue to experience problems with cognitive (i.e., thinking, organisation, memory) and general functioning, and report these problems to be distressing and disabling. Treatment of severe depression in New Zealand involves short-term treatment by Specialist Mental Health Services (SMHS) then discharge back to primary care. Following discharge, readmission to inpatient and outpatient services is very common. We are therefore interested in developing a treatment for people with severe depression that could be used to aid in cognitive and functional recovery following discharge from SMHS.
Does exercise lower systemic inflammation and improve chemotherapy efficacy in cancer patients? Dr Margaret Currie, University of Otago
Obese cancer patients tend to respond more poorly to chemotherapy and have more rapid disease recurrence and shorter survival times. One reason for this is that obesity leads to low-level chronic inflammation that fuels the development and spread of cancers. Little is known about how this systemic obesity-related inflammation affects the way cancer patients metabolise chemotherapy drugs. Therefore, this project aims to (1) measure circulating inflammatory proteins that may be used to identify patients who will respond poorly to chemotherapy and are at high risk of worse survival, (2) use cell culture studies to explore the way obesity-related inflammatory proteins may alter chemotherapy drug metabolism by the liver, and (3) perform an exploratory patient study that will use fitbits to monitor exercise during chemotherapy treatment, as well as measure circulating inflammatory proteins, patient liver enzyme activity and drug metabolism, and patient well being during treatment. This project will form the basis for ongoing studies at the University of Otago Christchurch into the potential benefits of moderate exercise during chemotherapy treatment.
Role and therapeutic potential of the novel DWORF peptide in heart disease
Dr Prisca Mbikou, University of Otago
Heart disease (HD) is a leading cause of death and disability in New Zealand, and new treatment options are needed. A recent breakthrough in genetic research concerning so-called non-protein-coding RNA has led to the discovery of a new class of proteins, one of which is called dwarf open reading frame (DWORF). This small protein is found almost exclusively in the heart where it may cause increased contraction of the heart muscle. DWORF levels are decreased in the hearts of people who have had heart attacks, suggesting it plays a role in the development of HD and may have potential as a treatment for restoring the impaired beating of damaged hearts. However, exactly how DWORF works and the effect on the heart of directly administering the protein is unknown. The goal of this research project is to investigate the effect of DWORF on heart function in normal and damaged hearts (using an ex vivo rat heart attack model), its levels in the heart in both settings, what proteins it interacts with, and how it operates. These highly original studies will further our understanding of this unique protein and might help in the development of a novel treatment strategy for HD
Reliability, validity and clinical application of temporal and amplitude analyses using pharyngeal high resolution manometry
Dr Kristin Lamvik, University of Canterbury and Rose Centre for Stroke Recovery and Research
After stroke, the majority of patients will experience difficulties swallowing, termed dysphagia. This is a critical impairment as it can place patients at increased risk of developing chest infections or even facing an increased risk of death. Thus, the proposed research programme will provide directives for refining the use of evaluation tools in the clinical assessment of swallowing problems. This is will be done by investigating a technique termed manometry, which measures throat pressure when swallowing. Manometry is important because it is one of the only ways to measure swallowing objectively, however, there is disagreement on the most valid and realiable way to analyse manometric data. The results from this study will have great importance both locally and globally. In Christchurch alone, there are two manometry systems used in clinical practice, one of which operates in the busy Christchurch Hospital. Thus, the results of this project will lead to an immediate improvement in patient care, helping to keep patients safe and swallowing effectively.
2015 Funded Projects
Major - Projects
Vitamin C requirements in Severe Infection - Dr Anitra Carr
Severe infection which results in a systemic inflammatory response (sepsis) is the leading cause of death in critically ill patients. The incidence of severe sepsis is increasing, and the outcome is poor, with mortality rates as high as 30-40%. Recent studies indicate a potential role for vitamin C in ameliorating severe infections (such as pneumonia) and sepsis. Vitamin C is a potent antioxidant and has potential anti-inflammatory properties. Preliminary research indicates that patients with sepsis have decreased vitamin C levels. The purpose of this study is to assess the levels of vitamin C in patients with pneumonia and sepsis over the duration of their stay in intensive care and to correlate these with levels of inflammatory biomarkers and patient outcomes. Vitamin C may prove to be a useful biomarker for the severity and progression of sepsis and the extent of deficiency of these patients will indicate requirements and will be used to inform the design of future clinical trials.
Red bloodcell vitamin C: a useful indicator of patient ascorbate status? - Dr Juliet Pullar
Vitamin C is an essential requirement of the diet in humans due to the evolutionary loss of the ability to synthesise it in the body. Vitamin C status is typically measured in a fasting-blood sample, which can be difficult for some people to provide, particularly those who are unwell. The aim of this project is to establish a method for measuring vitamin C status in non-fasting individuals using red blood cells. We will firstly optimize a procedure for assessing red blood cell vitamin C levels, and then measure the red blood cell vitamin C status of a group of surgical, sepsis and cancerpatients at Christchurch Hospital. Overall, this study will determine whether non-fasting red blood cell vitamin C levels are a reliable measure of patient vitamin C status.
The effects of resveratrol’s derivatives on VEGF, IL-6, IL-8 and NF-kB in ovarian cancer in vitro and in vivo studies -Dr Kenny Chitcholtan
Women with advanced ovarian cancer normally have a poor outcome because the tumour has spread within the abdominal cavity at the time of diagnosis. Most women with advanced disease show the sign of building up ofbody fluid; this becomes a clinical challenge for the current treatment management. Treatments currently available can prolong time of survival, but tumours become resistant to treatment and a cure is rare. In order to prolong time of patient survival, a new form of anti-cancer drugs, showing less side effects and being low cost, is urgently needed. Resveratrol is a food compound and has been found to show anti-tumour activity in a laboratory. But its anti tumour activities are uncertain in humans because resveratrol is highly metabolized and rapidly secreted from the body. Therefore, compounds that are structurally related to resveratrol may be useful to investigate their anti-tumour activities in human. We are very interested in derivatives of resveratrol and we want to investigate if these derivatives can exhibit anti-cancer activities in a laboratory before we could use them in humans.
RNA isoform profiling of breast cancer susceptibility genes - Dr Logan Walker
Routine diagnostic BRCA1 and BRCA2 gene screening for deleterious mutations is typically performed for individuals from suspected high-risk breast-ovarian cancer families to identify
the genetic cause for their disease. However, for most women with breast and ovarian cancer, the genetic changes contributing to their disease remain poorly understood. High-throughput genomic technologies are now being adopted by diagnostic laboratories worldwide, enabling mutation screening of BRCA1 and BRCA2, and other cancer related genes in a greater number of people. Determining the clinical meaning of newly discovered genetic changes will be a central challenge facing the future of genomic medicine. We will apply two powerful new technologies to measure the expression behavior of BRCA1 and BRCA2 activity in breast tumours from patients with and without a strong family history of cancer. Our proposal will assess if the inherited mutation status of these genes disrupts their behavior. Furthermore, our proposal will generate the first comprehensive gene expression profile of BRCA1 and BRCA2 in familial and non-familial breast tumours. The new knowledge derived from this proposal may facilitate the development of genomic-based protocols to evaluate genetic changes responsible for breast cancer and other inherited diseases.
Mycoplasma genitalium macrolide and fluoroquinolone - Dr Anja Werno
Mycoplasma species are the smallest free living bacterial forms. Mycoplasma genitalium is accepted as a human pathogen causing infections including urethritis and cervicitis. The first-line treatment of M. genitalium infections isazithromycin and in cases of treatment failure moxifloxacin is used. M. genitalium cannot be routinely cultured in the clinical laboratory and requires molecular techniques such as real-time PCR for detection and DNA sequencing to test for antibiotic resistance. The aim of this study is to evaluate whether the resistance rates warrant introduction of routine molecular resistance testing to assist with patient management. Monitoring of resistance rates will be useful to advise long-term treatment strategies around non-specific urethritis/cervicitis.
Identifying candidate RNA biomarkers for coronary artery disease - Dr Anna Pilbrow
Coronary artery disease (CAD) is a very common form of heart disease and is a leading cause of death in Canterbury. CAD develops when cholesterol-containing deposits (plaque) accumulate in the coronary arteries. As plaques build up, they decrease the flow of blood to the heart muscle, which can cause chest pain or a heart attack. The rate at which plaques build up varies between people making it difficult to identify those who may be at risk of a heart attack in the near future. Our research aims to identify new blood biomarkers for the presence of coronary artery disease, to allow screening and early detection of those at risk. Specifically, we will use a high-throughput genomics technology called next generation sequencing to measure levels of a newly-discovered class of molecules called long noncoding RNAs in 12 patients with stable coronary artery disease and 12 healthy controls from Canterbury. This in-depth screening study will help us identify candidate biomarkers to test in our existing, large cohorts of healthy volunteers and CAD patients in the future. Ultimately, our research may contribute to the development of new blood tests that will help predict those at impending risk of a heart attack.
Pilot study of biomarkers of outcomes from anticoagulants - Dr Paul Chin
Dabigatran (Pradaxa®) is a relatively new blood thinner medicine that is used to prevent clots. It was used in over 2,000 Cantabrians in 2014, and over 15,000 nationally. The main side-effect is bleeding. Dabigatran is currently used without any blood tests to check for the level of blood thinning. High levels of blood thinning may lead to bleeding, whereas low levels may lead to clots and strokes. Our study aims to find the ideal level of blood thinning with dabigatran. We will do this by doing blood tests on people taking this medicine, including those having clots and bleeds, as well as those who are well. In the future, knowing the ideal level of blood thinning with dabigatran will enable dabigatran doses to be adjusted so that high and low levels may be avoided.
C-Type Natriuretic Peptide and Renal Dysfunction - Dr Tim Prickett
Renal function is a major determinant of prognosis in patients presenting with heart failure or coronary artery disease. Recently we have discovered that fragments of a precursor molecule of C-type Natriuretic Peptide (CNP)are raised in blood as renal function begins to decline. Whether these changes result from diminished clearance or increased production by the kidney is unknown. The molecular identity of these peptide fragments and changes to their relative abundance in blood and urine in the failing kidney is unknown. The objectives of this proposal are twofold. Firstly, to identify the specific products of CNP gene expression in urine and plasma and thereby measure their clearance and renal production rates in health. Secondly, to measure both renal CNP production and clearance before, during and after induction of early renal and cardiac impairment induced by rapid ventricular pacing in 10 sheep. Collectively these studies will illuminate the mechanisms that lead to changes in CNP during the early phase of cardiac and renal impairment and may identify novel prognostic biomarkers suitable for detecting early renal failure (and implementing corrective treatments) in subjects with cardiovascular disease.
Amyloid and cognitive predictors of dementia in Parkinson’s - Dr Tracy Melzer
Cognitive decline and dementia are now recognised as an essential part of Parkinson’s disease, which ultimately becomes the most burdensome aspect of this disease. We know that those exhibiting mild cognitive impairments are at increased risk for developing dementia, but we have established that some individuals not showing cognitive impairments also exhibit increased risk. Here, we will perform advance positron emission tomography (PET) and MRI scans, and clinical evaluation in Parkinson’s patients with both high and low risk for developing dementia. We will determine whether PET imaging adds further information about an individual’s risk of future dementia. This will advance our understanding of this important issue and establish a useful and reliable tool for researchers and clinicians. It is critical that we can do this so that preventative treatments to protect against dementia can be targeted at the most appropriate patients when that treatment becomes available and also to select the right “at risk” Parkinson’s patients for trials of new treatments.
Pilot of methods to measure unmet secondary healthcare needs - Dr Phil Bagshaw et al
We have information on people who are treated in hospital but it is difficult to know how many people have health needs that are not being met. We know that some health services are over-crowded and that, over the last twenty years, a number of policies have limited peoples’ access to non-urgent care. This project will trial three population survey methods, and a method of getting information from GPs, to establish a reliable method of measuring unmet healthcare need in the community. We plan that in the future we will be able to measure unmet-need to assess the ongoing performance of the health system.
An investigation into the possible linkages between Vitamin C, Hypoxia and Cancer in Breast Cancer. Proposed analysis of Human Breast Cancer Tissue. - Professor Margreet Vissers (a jointly funded project with the NZ Breast Cancer Foundation)
The team will recruit breast cancer patients into future clinical studies, but first need to determine whether the inverse relationship between tumour ascorbate, the hypoxic response and tumour growth also applies to breast cancer. The team will carry out the analysis of a cohort of Tissue Bank breast cancer samples to determine whether the HIF-1 and ascorbate relationship exists in these tissues.
Summer Studentships 2015
- “I am HIV but I am not a patient”: Managing marginalized identities in health interactions. This study explores strategies that PLWHA use to manage stigmatization and marginalization in their health and support interactions
- Satisfaction with the Crisis Resolution Service: Consumer, family and referrer perspectives. The broad aim of the study is to evaluate the service satisfaction of consumers, families and referrers of consecutive people discharged from the Crisis Resolution Service over a period of four to six weeks.
- Genes that Predict Outcomes in Heart Failure. This study will investigate associations between several genetic risk markers and survival in 450 heart failure patients.
- Nanopore sequencing of repeat sequences in human DNA. This project seeks to explore and evaluate the ability of the MinION nanopore sequencer to correctly read and quantify a variety of human repeat DNA tracts
- The Dawn of Long Noncoding RNAs as Circulating Cardiac Biomarkers. This study investigates if plasma levels of three candidate long coding RNAs (IncRNAs) are predictors of incident cardiac events in a prospective cohort of healthy volunteers who were asymptomatic at recruitment
- The effect of Co-morbidities on Breast Cancer. This study determines the impact of co-morbidities such as Metabolic syndrome and obesity on molecular factors in breast cancer.
- ATP-Phosphoribosyl tranferase: a potential target of new anti-tuberculosis therapies?
- Measurement of urinary dityrosine as a quantitative marker of oxidative stress in patients
- Investigating the contribuition of herbicides to antibiotic resistence in important human pathogens
- Development of a bioassay for Angiotensinogen to Identify women prone to pre-eclampsia
- Sleep and technology use in 11-12 year old children: Does it impact on psychological wellbeing?
- 3D printing of intervertebral disc to treat spinal herniation
- Test of masticating and swallowing solids (TOMASS): validating behavioural observations of swallowing behaviour to objective instrumental assessment
- Longitudinal white matter tractography of progression of Parkinson's Disease
Here you can read the final reports from most of the CMRF-funded projects from the past few years.
Dr Logan Walker, University of Otago - RNA isoform profiling of breast cancer susceptibility genes
Dr Dean Harris, Christchurch Hospital - Potential biomarkers of 5FU cardiotoxicity
Dr Heather Parker, University of Otago - Superoxide dismutase and infection with Mycobacterium tuberculosis
Dr Louisa Forbes, University of Otago - Screening for Potent Inhibitors of Myeloperoxidase
Dr Katie Douglas, University of Otago - Effect of glucocorticoid administration on brain function in PTSD
Dr Philip Bagshaw et al, Canterbury Charity Hospital - Pilot study of Unmet Need
Dr Tracy Melzer, University of Otago - MRI to predict dementia in Parkinson's disease
Dr Daniel J Myall, University of Otago - Optimally predicting risk of cognitive decline in Parkinson's disease
Dr Jacqui Keenan, University of Otago - Unravelling the host innate response to enteral nutrition
Dr Suetonia Palmer, University of Otago - An evidence framework for protecting kidney function
Dr Wanting Jiao, Canterbury University - Developing new drugs for lung infections in cystic fibrosis
Dr Katie Douglas, University of Otago - Effect of glucocortocoid administration on brain function in PTSD
Dr Amy Scott-Thomas, University of Otago - Development of a non-invasive breath test for Legionnaires Disease
Dr Stephanie Bozonet, University of Otago - Regulation of endothelial cell death by Hypothiocynous acid
Dr Nicola Scott, University of Otago - Understanding how food leads to fat: the effect of dietary modification on the development of metabolic syndrome
Dr Judy McKenzie, University of Otago - Activated chronic Lymphocytic Leukaemia cells: suppressive effects on T Cell responses
Dr Carrie Innes, University of Otago, NZ Brain research Institute - Effect of obstructive sleep apnea on microsleeps and cerebral blood flow
Dr Tracy Melzer, University of Otago, NZ Brain Research Institute - Clinical tracking of cognition on Parkinson's Disease
Dr Logan Walker, University of Otago - Cytomegalovirus and Epstein Barr virus in Breast Cancer
Dr Lee Thompson, University of Otago - Role evolution and community pharmacy in Christchurch. Perceptions of pharmacists, GPs and pharmacy users
Dr Gabi Dachs, University of Otago - Chemotherapy response in obese mouse model with colorectal cancer
Dr Nadia Borlase, University of Otago - Thalmus in Parkinson's Disease ; a multimodal investigation of thalmic invovlement in cognitive impairment
Dr Judith McKenzie, University of Otago - Analysis of immunosuppression in Chronic Lymphocytic Leukaemia cells
Dr Claire Dowson, University of Otago - Cognitive / behavioural function in long term SSRI antidepressant use
Dr Leigh Ellmers, University of Otago - Effect of Chronic Urocortin2 treatment following experimental myocardial infarction
Dr Lisa Stamp, University of Otago - Effects of Frusemide on uric acid and oxypurinol in patients with gout
Dr Mark Richards, University of Otago - Renal impairment in decompensated heart failure
Dr Ruth Hughes, University of Otago - Screening for Type 2 diabetes in pregnancy
Dr Barry Palmer, University of Otago - Polymorphic variants of X-linked genes in heart disease
Dr Kenny Chitcholtan, University of Otago - Heliobacter Pylori outer membrane vescicles compromise the integrity of gastric epethelial cells
Dr Tim Woodfield, University of Otago - Alternative cartilage tissue engineering strategies; smart scaffolds and perfusion bioreactors
Dr Michael Sullivan, University of Otago - Validating biological markers for Hepatomblastoma: recovery of biomarkers (DNA and RNA) from parafin embedded tissues and development of tissue arrays
Dr Lisa Stamp, University of Otago - A Pilot Study of high dose allopurinol in the management of gout
Dr Judith McKenzie, University of Otago - Function of soluble CD83 in Chronic Lymphocytic Leukaemia
Dr Ross Kennedy, University of Otago - Determination of Effect site targets for Sevoflurane
Dr John Evans, University of Otago - Why do males die younger? Sex, steroids and yasopeptides
Dr Tim Prickett, University of Otago - NTpnoCNP as a marker of skeletal growth
Prof Margreet Vissers, University of Otago - A new role for Vitamin C in control of hypoxis response in cancer cells