Laurenson Bequest Award

The effects of lithium on rat sciatic nerve recovery following crush injury

Associate Professor Graeme Hammond-Took, Associate Prof Anthony Poole and Dr Koji Yamanoto (Honorary Research Fellow) (Medicine) - $13,564

Demyelination (loss of the myelin sheath, the insulating layer around many nerve fibres) is a prominent feature of diseases like multiple sclerosis and Guillain-Barre syndrome. The drug lithium has recently been shown to stimulate both myelin formation and elongation of primary cilia, small sensory “antennae” found on most cell types including myelinating Schwann cells. We will study peripheral nerves following crush injury, with and without lithium treatment, using confocal and electron microscopy. Staining for ciliary proteins will be used to determine the role of primary cilia in myelin repair and the potential for lithium therapy in myelinating disorders.

 

Exploiting palladium nanocages for cisplatin drug delivery.

Dr James Crowley and Dr Gregory Giles (Chemistry & Pharmacology & Toxicology) - $25,375

Every year in New Zealand, cancer affects around 18,000 new patients, and kills >8,000 people. Cisplatin is a widely used anti-cancer agent which is very effective against a variety of tumors. However, this platinum based drug has two major drawbacks, namely general toxicity (leading to undesirable side effects) and drug resistance. We have synthesized novel nanoscale cage molecules that are able to bind two molecules of cisplatin within their central cavity. The aim of this research is to show that these palladium nanocages can be exploited to deliver cisplatin drugs selectively to tumor sites thereby increasing the efficacy and safety of these platinum drugs. This could potentially result in new, more effective therapeutic protocols for cisplatin administration in the clinic.

 

Cubosomes: Novel lipid-based particulate carriers to improve delivery and efficacy of anti-epileptic drugs in drug-resistant epilepsy.

Dr Shakila Rizwan and Associate Professor Ben Boyd (Monash University) (Pharmacy) - $22,500

Epilepsy is a common brain disorder with up to 40% of sufferers failing to achieve good seizure control. One possible reason for treatment failure is that high enough levels of anti-epileptic drugs (AEDs) don’t reach the brain. A promising strategy to increase brain AED concentrations is by incorporating them in carriers. The aim of this study is to investigate whether cubosomes, a novel lipid based carrier will facilitate the uptake of AEDs into the brain.

 

Diagnosing mild iodine deficiency in New Zealand adults.

Dr Shelia Sheaff & Associate Professor Patrick Manning (Human Nutrition & Medicine) - $16,320

Iodine is required to make thyroid hormones needed for normal growth and development, particularly of the brain. A lack of iodine in the diet is still one of the most common nutrient deficiencies in the world today. From the mid 1990s, mild iodine deficiency re-emerged in New Zealand prompting the government to make the addition of iodised salt to bread compulsory in 2009. However, people who eat little or no bread remain iodine deficient. Currently, we can only measure iodine deficiency in groups of people. This project will determine if a blood component called thyroglobulin can be used to diagnose mild iodine deficiency in adults.

 

Measuring the temporal impact of exclusive enteral nutrition on gut microbiota and urinary metabolite profiles of Crohn’s disease patients: a pilot study.

Professor Gerald Tannock and Associate Prof Richard Gearry & Professor Andrew Day (Medicine Christchurch) (Microbiology & Immunology & Medicine) - $12,000

The bacteria that live in the bowel appear to drive the chronic inflammation seen in Crohn’s disease. The composition of the bacterial collection in stool of newly diagnosed, young adult, Crohn’s disease patients will be determined and correlated with urinary chemical profiles. Changes in these bacterial and chemical profiles, resulting from consuming a fluid formula as exclusive enteral nutrition (EEN), will be recorded. This pilot study will reveal whether EEN changes the bacterial content of the bowel with improved clinical outcomes, and whether the products of bacterial metabolism excreted in urine are altered consequently and could be used as indicators of successful treatment.

 

Impact of furosemide on uric acid homeostasis (synthesis and transport) in humans.

Dr Andrew Bahn and Associate Professor Lisa Stamp (Department of Physiology & Department of Medicine) - $27,738

Elevated serum urate (SU) levels in humans are required for the development of gouty arthritis. Lowering SU to <0.36mmolfL is critical for the long-term management of gout. The most common treatment to reduce SU is allopurinol, an inhibitor of xanthine oxidase (XO). Hypertensive gouty patients are frequently treated with furosemide, which interacts with allopurinol making urate lowering more difficult. The molecular background of this effect is unresolved. AMP-kinase (AMPK) is a regulator of urate transport in the kidney, which is the main contributor to SU homeostasis. We aim to examine the molecular effect of furosemide on XO and AMPK to understand this drug-drug interaction. This study will help to improve treatments for patients with gout receiving furosemide.

 

Utilising nanotechnology for producing effective anticancer therapy against breast cancer

Dr Khaled Greish and Associate Professor Rhonda Rosengren (Department of Pharmacology & Toxicology) - $18,018

In New Zealand, every year Breast cancer affects around 2500 new patients, and kills more then 600 patients. One third of breast tumors lack a protein called the estrogen receptor, resulting in lack of effective management, leading to aggressive recurrence and metastasis. We have synthesized novel curcumin derivatives with high efficacy against this type of cancer. Within the scope of this grant we aim to demonstrate selective delivery of these novel drugs to breast tumors models with nanotechnology. Nanotechnology can not only increase the efficacy but also the safety of our compounds, and potentially result in a clinical drug for those patients.

 

How do blood pressure stimulating-drugs affect the diabetic heart?

Dr Regis Lamberts and Dr Peter Jones (Department of Physiology) - $16,505

Diabetes is often associated with an increase in heart complications, especially during surgery. Heart function is governed by calcium, which is controlled by calcium handling proteins and catecholamines (adrenaline). In diabetes the control of the heart by these factors is reduced. We will measure changes in calcium handling proteins in response to catecholamines in heart biopsies from diabetic patients, and in hearts from diabetic animals in which we will also relate this to functional measurements. This will yield crucial knowledge of why catecholarnines poorly regulate the diabetic heart and help to develop new strategies to optimise the use of catecholaminergic drugs during surgery.

 

Investigating the anti-inflammatory response of novel bioactive lipid vesicles to treat inflammation at the blood-

Dr Shakila Rizwan, School of Pharmacy, University of Otago

Inflammation at the blood-brain barrier (BBB), a cellular barrier which safeguards the brain from the rest of the body, is an early hallmark of many neurodegenerative disorders. A group of fatty molecules known as NAEs promote neuroprotection and may slow down the progression of neurodegenerative disorders and thus have the potential to be transformative therapies. However, these molecules are challenging to formulate into a medicine and target to the BBB, which we have addressed with formulation science. This study will now investigate the anti-inflammatory properties of our new therapeutic formulation.

 

Lithium-induced changes in renal tubular cell regulatory pathways

Professor Robert Walker, Medicine, Dunedin School of Medicine

Lithium is an effective agent used to manage bipolar disorders. However, long-term lithium therapy can be associated with the development of chronic kidney disease. Our research group has been investigating how lithium induces kidney damage. Lithium induces changes in the specialised kidney cells responsible for handling salt and water. In addition, lithium is associated the slow development of fibrosis (scarring) in the kidney. We plan to explore the pathways that lead to the lithium-induced changes. Understanding these pathways could lead to new ways to treat and prevent chronic kidney disease.

 

Mycobacteria-responsive prodrugs to combat drug-resistant tuberculosis

Dr Allan Gamble, School of Pharmacy, University of Otago

M tuberculosis is a bacterium that causes tuberculosis, a disease that infects more than 10 million people per year. Patients are treated with a mixture of drugs but as the bacteria mutates the drugs no longer work. To fight drug-resistant strains of M. tuberculosis, new drugs and drug delivery methods are needed. Two new classes of drugs have been shown to kill the bacteria, but clinical challenges exist. The drugs need to be in the bacteria at the exact same time, and one of the drugs in the combination is toxic to human cells. By attaching a linker we can convert the drugs into inactive forms (prodrugs), and trick the bacteria to activate each drug individually, killing itself and sparing human cells. Successful prodrug activation in this project will enable us to explore co-drugs, inactive forms of the drugs linked together for simultaneous delivery and bacteria-specific activation.

 

Pharmacological activation of the intrinsic regulator of heart metabolism for a healthy heart aging

Associate Professor Rajesh Katare, Physiology, University of Otago 

Heart disease will result in 40% of all deaths in adults aged 75 and above, and rank as the leading cause. Aging impairs heart metabolism by reducing glucose transport. We have recently identified that reduced acetylcholine synthesis in aged heart muscle cells is associated with reduced glucose transport. In the current proposal, we aim to investigate if restoring acetylcholine bioavailability in the aged heart by preventing its breakdown improves recovery following a heart attack. Results from our study will provide knowledge for a novel treatment option for aging hearts by targeting acetylcholine bioavailability.

 

Ketamine therapy for ‘neurotic’ disorders: is there a single mechanism?

Professor Paul Glue (Department of Psychological Medicine, Dunedin School of Medicine), Dr Shabah Shadli & Professor Neil McNaughton (Department of Psychology)
Neurotic disorders (anxiety and depression), are the most prevalent mental disorders in New Zealand, USA and Europe. Neurotic disorders have high chronicity, are highly disabling, have severe impact on societies, with suicidal ideation, suicide attempts and costs to public health. But, currently available medications are ineffective in almost 35 to 40% anxious/depressed patients; making them treatment resistant. Hope is raised by ketamine. We found that ketamine’s therapeutic effect in GAD and SAD cases where other treatments were ineffective correlated with decreased theta frequency rhythms in frontal brain activity. We will test if ketamine produce similar therapeutic changes in all neurotic disorders.

 

Targeted nitric oxide donor drugs to cure breast cancer

Dr Gregory Giles, Professor Rhonda Rosengren & Dr Niroshini Giles (Department of Department of Pharmacology and Toxicology, School of Biomedical Sciences), Dr Carol Bussey (Department of Physiology, School of Biomedical Sciences)
Photodynamic therapy is a technique that uses light to activate a drug inside a tumour; the activated drug then proceeds to destroy the tumour from within. As the applied light can be selectively focused on the cancer, the drug only activates within the tumour environment. This causes localised anti-cancer action, whilst avoiding side effects in other areas of the body. We have recently developed a new lead compound for photodynamic therapy, tDodSNO, which has promising activity against cancer cells. We now propose to evaluate tDodSNO in animal and cell culture models of breast cancer, a disease which urgently needs new treatments as patients have a very poor prognosis.

 

Wholegrain structure and control of type 2 diabetes: randomised crossover trial

Dr Andrew Reynolds & Professor Jim Mann (Department Medicine, Dunedin School of Medicine)

We have considered the effects of wholegrain processing, specifically milling, on glycaemic control in free-living adults with type 2 diabetes with a randomised crossover trial of two interventions of two-weeks duration. Thirty one participants were provided wholegrain bread, oats, and brown rice that differed in their degree of processing. In one intervention these wholegrain foods were minimally processed, in the other intervention they were finely milled.

Participants consumed on average 5.5 serves of wholegrain foods a day and there was no difference in their reported energy intake. Blood glucose responses after meals and blood glucose variability during the day were significantly better when participants ate the minimally processed wholegrain foods when compared with those that were finely milled. These results indicate that dietary advice for those with type 2 diabetes should promote the consumption of minimally processed whole grains.

 

Assoc Prof Mark Thompson Fawcett (Department of Surgical Sciences, Dunedin School of Medicine), Prof Gerald Tannock & Mr Blair Lawley (Department of Microbiology & Immunology, School of Biomedical Sciences)
Probiotics, or good bacteria, can improve health. Some patients with inflammatory bowel disease have their entire large bowel removed with surgery. To avoid a stoma bag, a pouch is made out of the end of the small bowel (ileum) and joined to the anus to make an ‘ileal’ pouch. Half of these patients develop an inflammatory condition in their pouch called pouchitis. After a decade of careful scientific investigation we have successfully produced a specific probiotic for pouchitis. A small pilot study has been successful and we now seek funding to do a larger national study to test the probiotic’s effectiveness properly.

 

Dr Jack Dummer, Dr Ben Brockway (Department of Medicine, Dunedin School of Medicine), Dr Shyamal Das (School of Pharmacy) & Prof Philip Hill (Department of Preventive & Social Medicine, Dunedin School of Medicine)
Tuberculosis (TB), caused by Mycobacterium tuberculosis , is a disease mainly of the lungs. Rifampicin, a first-line anti-TB medicine, is given orally for 6 months, and only a small fraction of the dose goes to the lung. Direct delivery of rifampicin to the lungs by inhalation can achieve high levels in the lung and in blood to kill M. tuberculosis more effectively throughout the body. In this project, we will produce rifampicin dry powder for inhalation in a GMP site and conduct a clinical study in healthy human participants to confirm safety and determine the optimal dose for inhalation. This will enable design of clinical studies combining inhaled and oral rifampicin in TB patients, aiming to shorten the duration of treatment.

 

Dr Ben Wheeler (Department of Women’s & Children’s Health, Dunedin School of Medicine), Ms Deanna Beckett & Dr Carolina Loch (Department of Oral Sciences, Faculty of Dentistry), Dr Erin Mahoney (Department of Paediatrics, University of Otago Wellington) and Mr Andrew Gray (Department of Preventive & Social Medicine, Dunedin School of Medicine)
New Zealand children, particularly those living in the South Island, are at high risk of vitamin D deficiency . Deficiency during tooth development may result in developmental defects and dental decay . Data from a 2012 randomised controlled trial are available for 126 women and their infants, including vitamin D status at multiple time points during pregnancy and after delivery. The children from this study, now between five and seven years of age, will be losing their first baby tooth and gaining their first permanent molars. We aim to study potential childhood dental consequences of vitamin D deficiency during pregnancy and early life.

 

Assoc Prof Ivan Sammut, Dr Joanne Harrison & Dr Morgayn Read (Department of Pharmacology & Toxicology)
Over 800,000 surgical interventions requiring cardiac bypass are conducted globally each year. Whilst for the majority, the outcome is favourable, the procedure can inevitably result in damage to the heart through ischaemia-reperfusion injury. This exacerbates the patient’s condition and ultimately affects mortality. We have developed novel low-dose carbon monoxide releasing compounds that can prophylactically protect hearts from ischaemia-reperfusion injury. While this is a valuable finding, we wish to confirm that the same protection can be obtained in diseased hearts typically seen in bypass patients. We will trial our lead compound in a model of ischaemia-reperfusion conducted in enlarged hearts resulting from chronic hypertension. Ultimately this intervention will be developed as an adjunct therapeutic for use in cardiac surgery.

 

Dr John Ashton  (Department of Pharmacology & Toxicology)
Lung cancer is responsible for more deaths than any other cancer in New Zealand. It has recently been discovered that the anaplastic lymphoma kinase (ALK) receptor is overexpressed in 2-5% of lung cancer patients. While inhibiting this protein improves survival, resistance usually develops, within a year, frequently because of the overexpression of other proteins, such as IGF1-R. We seek to develop a model of metastatic lung cancer in order to test a novel combination strategy to prevent the development of resistance to ALK inhibitors. This will aid in the development of more effective treatment strategies for lung cancer patients.

 

Assoc Prof James Crowley (Department of  Chemistry), Dr Heather Brooks (Department of Microbiology & Immunology) and Dr Gregory Giles (Department of Pharmacology & Toxicology)
Resistance of microbes to currently used antimicrobial drugs represents a major threat to human health. We propose to synthesise a small family of platinum(ll) “click” complexes and examine their antimicrobial activity against a range of resistant bacteria. Additionally the mode of action and cytotoxicity of these “click” metal complexes will be characterised. The resulting new class of metallo-antimicrobials could lead to antibacterial agents that display novel modes of action.

 

Prof Sally McCormick (Department of Biochemistry) & Prof Samir Samman (Department of Human Nutrition)
Cardiovascular disease (CVD) is responsible for over 30% of deaths in New Zealand per year. Statin drugs reduce CVD death rates by reducing levels of low density lipoprotein cholesterol (LDL-C). However, statins alone do not adequately reduce CVD mortality, and cause side-effects in some individuals that preclude their use. Ribose-cysteine is a promising antioxidant compound that shows both antioxidant and LDL-C lowering properties in animals.  We hypothesise that ribose-cysteine has the potential to protect individuals at risk of CVD. We propose to perform the first ribose-cysteine supplementation trial in humans to evaluate its effects.

 

Title of Project: Hormonal restraint of hedonic eating behaviour – LA 337; Awarded December 2014; Project commenced July 2015.

Leptin’s hunger-suppressing actions in the hypothalamus are well characterised, yet the mechanisms by which leptin modulates the midbrain dopamine (DA) system to suppress hedonic feeding remain less clear. A subset of midbrain DA neurons express leptin receptors (Lepr), and direct leptin administration to the midbrain reduced food intake and suppressed DA neuron firing in rats, suggesting leptin may directly modulate DA neurons. To further explore whether direct leptin-DA signaling modulates appetitive behaviour, we generated transgenic mice in which Lepr were expressed exclusively in DA neurons. We then compared weekly body weight, daily food intake (standard chow diet), hyperphagic feeding (1-hr fully sated access to a high-fat high-sugar diet), and leptin-induced suppression of feeding between these Lepr^DAT mice and their wild-type (Lepr^CON) and Lepr^NULL littermates. As expected, both the Lepr^NULL and Lepr^DAT mice exhibited significantly increased body weight and food intake compared to the Lepr^CON mice. Interestingly, the Lepr^DAT mice exhibited significantly increased post-weaning body weight compared to the Lepr^NULL mice (3-8 weeks), yet no differences in adulthood body weight or food intake were observed. Furthermore, neither the Lepr^NULL nor Lepr^DAT mice exhibited a reduction in 4-hr food intake when treated with leptin (5 mg/kg) vs. saline, whereas the Lepr^CON mice exhibited a significant leptin-induced decrease in food intake. Lastly, Lepr^DAT mice appear to exhibit a blunted hyperphagic response compared to the Lepr^NULL mice, suggesting that their increased weight gain may be due instead to metabolic changes. While still preliminary, it appears direct leptin-DA signaling does indeed play a role in modulating appetitive behaviour.

 

Title of Project: The cardio-renal syndrome: targeting aldosterone inhibition to reduce cardiac and renal injury – LA 340; Awarded December 2014; Project commenced April 2015.

There is now increasing awareness that heart attacks and heart failure can produce chronic kidney injury but the mechanisms are not well understood. Heart and kidney disease have common causative features, hypertension being one of the most significant. Combined kidney and heart disease has a worse outcome than heart failure alone (the cardio-renal syndrome). Using a hypertensive rat model, we have investigated the changes in cardiac, arterial and renal function and injury following a heart attack and how aldosterone blockade by spironolactone may modify the adverse effects. Reducing the impact of heart failure and kidney injury should improve survival.

 

Title of Project: The mechanism of action of glucocorticoids revealed through changes in DNA methylation – LA 339, Awarded December 2014; Project commenced February 2015.

Glucocorticoids such as dexamethasone have been widely used for decades to treat a wide range of cancers. They are a vital component of chemotherapy especially for lymphoid cancers including childhood leukaemia, lymphoma and myeloma. Despite their importance, glucocorticoid use is limited by their numerous side effects and by the development of resistance. Many of the effects of glucocorticoids are mediated through changes in gene activity. Surprisingly, we have found marked changes in epigenetic marks on numerous genes in response to glucocorticoid treatment of a leukaemia cell line. Confirmation of these glucocorticoid-induced epigenetic changes and identification of the genes affected will help to identify strategies to target specific pathways to enhance treatment, bypass therapeutic resistance and avoid side effects.

 

Title of Project: Use of a dual COX/LOX inhibitor for treatment of cancer – LA 338; Awarded December 2014; Project commenced January 2015.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to prevent inflammation. They have also been investigated for use to prevent and even treat cancer. The use of these drugs in cancer is still experimental and preliminary preclinical work from our group has shown that a new type of NSAID with a more broad-spectrum activity can treat cancer when used in combination with a cancer vaccine. This research project will eventually tailor the treatment regime, and how the drug is delivered, in order to optimise anti-cancer activity and patient quality of life.

 

Department of Anatomy: Hormonal restrant of hedonic eating behaviour
We all know how difficult it can be to resist a second helping of a delicious dinner, or turn down that piece of cake calling your name. However with obesity and its associated health problems on the rise, saying no to those tempting treats is becoming increasingly important.

Areas of the brain are known to have a physiological control over our body weight by stimulating and inhibiting food intake based on our body’s energy needs. However researchers have become aware that eating for pleasure rather than energy (hedonic eating) contributes a big part to the problem of obesity. With support from a Laurenson Grant (administered by the Foundation), Associate Professors, Greg Anderson, John Reynolds and Dr Maggie Evans are investigating the brain (neural) pathways involved in hedonic eating. Rewarding experiences cause the release of dopamine in certain areas of our brain, making us want to have these experiences again. Hedonic eating also causes the release of dopamine, triggering the neural reward pathways which stimulate overeating and the feeling of ‘food addiction’ that many people experience.

During their research project (funded in November 2014), Greg, John and Maggie will investigate how hormones involved in regulating the physiological control of eating, also affect an area of the brain containing dopamine cells. The hormones leptin and insulin normally signal our brain to say we don’t need any more energy (food). The research will focus on how leptin and insulin act in the brain to control release of dopamine during hedonic eating. The researchers believe that the release of dopamine while eating for pleasure is increased in obesity, motivating us to eat more, and that leptin and insulin might be the key to changing the feeling of reward our brain experiences and decreasing our desire to overeat.

This exciting research will hopefully take us a step closer to understanding how to break our ‘food addiction’ and step away from the dinner table!

 

Anatomy: Treatment of brain injury due to extreme prematurity: Is melatonin protective?
$29,931
This translational research aims to investigate whether treatment with melatonin rescues the brain injury of extreme prematurity. Specifically, we will investigate if treatment with melatonin prevents the death of brain glia (i.e. pre-oligodendroglia), and prevents myelin and memory deficits, in an innovative, clinically relevant animal model. The animal model was developed by Associate Professor Oorschot and her research team at the University of Otago. This model was published1 in the prestigious international journal, the Journal of Neuroscience, in July 2013. A positive outcome would drive clinical trials to develop an effective treatment for brain damage due to extreme prematurity.

 

Pharmacology & Toxicology & Anatomy: Using raloxifene in a drug combination for the treatment of metastatic hormone refractory prostate cancer
$29,265
Men diagnosed with prostate cancer that does not respond to hormone therapy have a poor prognosis and the current treatment options have not significantly increased patient survival. This project will investigate the ability of a new combination therapy, which we have recently developed, to suppress prostate tumor growth in vivo. We already know that this drug combination kills 99% of prostate cancer cells in culture and works by isolating two key proteins responsible for cell growth and cancer spread to other organs. This project examines the next critical step, which is to determine whether these effects in cell culture will also occur in a mouse model of aggressive prostate cancer.

 

Pharmacology & Toxicology: Utilizing nanotechnology for improving anticancer therapy of pancratic cancer
$19,882
Pancreatic cancer is a fatal type of cancer with the number of annually diagnosed cases almost equal to the annual death rate. The disease is even more lethal among Maori who demonstrate 50-100% higher incidence rate than non-Maori. Pancreatic cancer is especially difficult to treat because it has limited blood vessels to supply anticancer drugs. In this work we will test a new system made of two styrene maleic acid (SMA) nanomicelles. The first micelle will encapsulate a nitric oxide donor to cause vasodilation in tumor blood vessels and hence enhance the delivery of a second SMA micelle encapsulating the chemotherapeutic agent.