Awarded Project grants

Project grants awarded 2014

  • 31 Dec 2014

CREATING NEURAL BRIDGES: A CONDUCTING POLYMER NEUROTRANSMITTER RELEASING SYSTEM – 1114010 ($150,215 – 2 years)

Dr Darren Svirskis, A/Prof Johanna Montgomery, Prof Jadranka Travas-Sejdic
School of Pharmacy, University of Auckland

Advancements at the Brain-Machine interface have enhanced human life, for example cochlear implants to enable hearing and deep brain stimulation to alleviate symptoms of Parkinson’s disease. We hypothesise that neurotransmitter loaded Conducting Polymers (CPs) can function as neural bridges, modifying neuronal action potential firing patterns and facilitating neuronal communication. We propose to develop a glutamate releasing CP responsive to the intrinsic electrical activity of neurons. We will culture neurons together with CPs in vitro, forming neural bridges. For the first time, we will study how action potentials in living neurons alter the properties of stimuli-responsive CPs. Using these neural bridges, we will determine if the firing of one neuron can trigger a CP to release a neurotransmitter and subsequently influence the firing rate of a second neuron. The data from this research will provide a platform to develop new treatment strategies for conditions of abnormal neuronal signalling, such as autism, epilepsy, nerve injuries and hereditary sensory impairments. The methods developed in this research could be used to study and manipulate other electrically active cells such as those found in the heart and gastro-intestinal tract.

 

IMPROVING PATIENT RECOVERY AFTER ABDOMINAL SURGERY USING A LONG ACTING LOCAL ANAESTHETIC IMPLANT – 1114011 ($154,940 – 2 years)

Dr Manisha Sharma, Prof Andrew Hill, Dr Darren Svirskis
School of Pharmacy, University of Auckland

Major abdominal surgery is associated with post-operative pain, fatigue, long hospital stays and significant resource consumption. Currently, patients are commonly administered analgesics (opioids), or local anaesthetics during and after surgery. The use of opioids is associated with serious systemic side effects. Local anaesthetics have shown better patient recovery as they act by blocking nerve conduction from the site of surgery. However, the local anaesthetics are administered as a solution using an elastomeric infusion-catheter device. These infusion devices, use bulky, expensive pumps, and require technical expertise of trained staff throughout the period of therapy. In addition, this system may also be complicated by microbial infection or blockage. This not only causes patient inconvenience but also increases the duration of stay in the hospital, further adding to healthcare costs. This proposal aims to develop a polymeric non-biodegradable implantable system loaded with local anaesthetic to treat post-operative complications. These bioactive implants will release drug at desirable rates, over an extended period of time. Drug delivery technologies like these would not only benefit patients in New Zealand, but will also have high impact globally by enhancing recovery after surgery.

 

MAXIMIZING THE POTENTIAL OF IDO1 INHIBITORS TO INDUCE DURABLE, LONG-TERM REGRESSION OF TUMOURS – 1114012 ($159,300- 2 years)

A/Prof Lai-Ming Ching, A/Prof Ian Hermans, A/Prof Brian Palmer
Auckland Cancer Society Research Centre, University of Auckland

Recent breakthroughs in cancer therapy, using agents that unleash the immune system, have enabled patients with previously incurable cancers such as metastatic melanoma, to live disease-free for more than 10 years. We have developed a new class of agents that inhibit an immunosuppressive enzyme called IDO1. In this research we aim to explore multiple approaches that may increase the potential of these IDO1 inhibitors to treat cancer. We aim to combine these novel IDO1 inhibitors with other investigational immunotherapies; to identify the best combinations that will provide the most durable responses against preclinical models of lung carcinoma, melanoma and glioblastoma. We will test IDO1 inhibitors in combination with antibodies to immune checkpoint antigens as well as in combination with anti-cancer vaccines being developed for treatment of melanoma and gliomas.

 

FINDING INHIBITORS FOR MenD FROM A HUMAN PATHOGEN – 1114013 ($141,280 – 2 years)

Dr Jodie Johnston, Prof Margaret Brimble, Dr Daniel Furkert
School of Biological Sciences, University of Auckland

Mycobacterium tuberculosis (Mtb) is the bacterium that causes tuberculosis (TB). Worldwide, TB is a big health problem, causing more deaths per year than any other infectious disease apart from HIV. In NZ, TB disproportionately affects migrants, lower socioeconomic groups and Māori. It is a difficult disease to eradicate as the bacterium can “hide” in the body in a latent state. Multi-drug resistant and extremely-drug resistant strains have also emerged, so new drugs are desperately needed. We aim to develop inhibitors for MenD, an enzyme vital for production of vitamin K2 (menaquinone) in Mtb and essential for the survival of the bacterium. No MenD enzyme exists in humans, so drugs targeted against this enzyme are less likely to be toxic. Our recent 3D structure of MenD, combined with computational modelling, gives us a knowledge base on which to select a set of potential inhibitor compounds. We will then develop an assay to screen these compounds and find those that are inhibitors. We will then use X-ray crystallography to discover how the best inhibitors bind to MenD, characterise their interactions and see how to improve them. The Mtb MenD inhibitors we discover could become part of the next line of anti-TB treatments.

 

PERIOPERATIVE VASCULAR EVENTS IN UNRECOGNISED OBSTRUCTIVE SLEEP APNOEA

A/Prof Timothy Short, Dr Ivan Bergman, Dr Joyce Tai, Dr Maartje Tulip – 2114014 ($157,880 – 2 years)
Dept of Anaesthesia & Perioperative Medicine, Auckland City Hospital

Obstructive sleep apnoea (OSA) is the most common sleep-related breathing disorder. It is increasing in prevalence. OSA is estimated to be present in 9% of women and 17% of men, but is frequently undiagnosed. OSA has been associated with cardiovascular problems including stroke, heart attack, cardiac arrest and abnormal heart rhythms, and patients with untreated OSA are more likely to die from these conditions. There is currently little data about the effect of OSA in surgical patients, although there is a trend towards increased risk of cardiovascular complications. The Postoperative Vascular Events in Unrecognized Sleep Apnoea Study (POSA) is an international multi-centre study of the effects of undiagnosed OSA on vascular complications in patients undergoing major surgery. The study will include patients over the age of 45 who are undergoing major non-cardiac surgery, and who have at least one risk factor for post-operative vascular events. All patients will have an overnight sleep study pre-operatively to assess whether they have OSA, and to determine its severity. Post-operatively the patients will be followed closely for the first three nights to assess the impact of breathing on postoperative complications.

 

PAIN IN THE BACK! DECIPHERING WHICH CELLS DRIVE INTERVERTEBRAL DISC DEGENERATION – 1114015 ($147,194 – 18 months)

Dr Sue McGlashan, Ms Taryn Saggese, A/Prof Ashvin Thambyah
Dept of Anatomy with Radiology, University of Auckland

Intervertebral disc degeneration is a major cause of back pain. The intervertebral disc consists of an outer fibrous ring, the annulus fibrosus, which surrounds an inner gel-like centre, the nucleus pulposus. Strong annular fibers contain the nucleus pulposus and distribute pressure evenly across the disc, whereas the nucleus pulposus acts as a shock absorber. With degeneration, the nucleus pulposus becomes fibrous and stiff, unevenly transferring loads to the annular walls creating areas of high stress, increasing the risk of disc herniation. Although changes in the nucleus pulposus are thought to initiate disc degeneration, how this occurs is still poorly understood. This study will examine the role of the 2 major cell types present in the nucleus pulposus to determine which cells are susceptible to changes in nutrient supply to the disc (which occurs with ageing) and excessive/inappropriate mechanical loads (e.g. such as poor posture or lifting heavy weights). The findings of this study will advance our understanding of how disc degeneration develops and help develop cell based therapies.

 

NATURAL PRODUCT BASED ANTIBODY-DRUG CONJUGATES (ADCs) – 1114016 (158,317 – 2 years)

Prof Margaret Brimble, Dr Paul Harris, Dr Kuo-yuan (Greg) Hung, A/Prof Adam Patterson, Dr Jeff Smaill
School of Chemical Sciences, University of Auckland

Breast cancer is a common cancer that affects approximately 1 in 9 women in New Zealand. Current breast cancer treatments include surgery, radiotherapy, and chemotherapy. Patients undergoing breast cancer chemotherapy often experience unpleasant side effects as healthy cells are also targeted by the cytotoxic drugs used in the treatment. Antibody-drug conjugates (ADCs) serves as a powerful tool to deliver cytotoxic compounds selectively to tumour cells without causing significant damage to healthy tissues. The antibodies incorporated within the ADC system specifically bind to the corresponding antigens present on cancer cells, hence leading to a significant reduction of the common systemic toxicities associated with chemotherapy. With ADCs being the future ‘holy grail’ for cancer therapy, there is an urgent need to identify novel potent and selective cytotoxins for conjugation to monoclonal antibodies. Culicinin D is a naturally occurring peptide that exhibits potent toxicity against PTEN-negative cancerous breast cells thus providing an exciting new cytotoxin for further development. The synthesis of culicinin D, and analogues thereof, will be undertaken in order to evaluate their potential for use as ADCs. In this study we aim to ultimately create effective ADCs that can be used to treat patients with PTEN-negative breast cancer.

 

MRI AS BIOMARKER FOR RHEUMATOID ARTHRITIS – 1114001 ($159,560 – 2 years)

Prof Fiona McQueen, Dr Peter Chapman, A/Prof Nicola Dalbeth, A/Prof Anthony Doyle, Dr Karen Lindsay
Dept of Molecular Medicine and Pathology, University of Auckland

The management of rheumatoid arthritis (RA) has undergone a revolution in the past decade. New drug therapies can markedly reduce joint pain and many patients can achieve clinical remission with reduction in long-term joint damage. It is important to assess patients’ responses to different drug regimens. MRI scanning is an ideal imaging biomarker as it reveals inflammation affecting the lining of the joint (synovitis) and the bone beneath (bone oedema or BME) plus joint damage (erosions and cartilage thinning). The Auckland Rheumatology Imaging group has an established track record in MRI research in RA. We now plan to move our expertise into the clinical arena. New Zealand rheumatologists use specific drug regimens (conventional and biological), to try and achieve remission in a “Treat-to-Target” approach. They monitor patients’ progress using the Disease Activity Score (DAS) which quantifies joint inflammation clinically. The aim of this study is to obtain MRI inflammation scores (synovitis, BME, tenosynovitis) before and after each drug intervention, to see whether changes in MRI scores mirror changes in the DAS. We intend to compare MRI and DAS responses between 2 groups of patients: those receiving conventional disease-modifying antirheumatic drugs (cDMARDs) and those receiving biological therapies (bDMARDs).

 

A NON-INVASIVE TEST OF EMBRYO QUALITY – 1114002 ($120,285 – 2 years)

Dr Lynsey Cree, Prof Larry Chamley, Prof Peter Stone, Dr Matthew VerMilyea
Dept of Obstetrics and Gynaecology, University of Auckland

In vitro Fertilisation (IVF) is a commonly used technique for infertility and its use is rising due to women delaying child bearing. Annually 350,000 babies are born using this technique, however success rates are still low. Developing techniques to select the best embryo for transfer in order to maximise the likelihood of a healthy live baby represents one of the major challenges in reproductive medicine. Recent data suggests that embryos expel genetic material into the media in which they are cultured. This is a novel finding that has the potential to provide a non-invasive way to look at the genetic complement of the embryo. Current techniques used to do this are invasive and some may harm the embryo. Our research aims to investigate whether this genetic material, located within the media, can give meaningful data of embryo quality and whether it can be used to select only those embryos with the correct chromosomal makeup. This is particularly important for older women whose embryos are more likely to have an incorrect chromosomal makeup. Selecting embryos with the correct chromosomal makeup will increase IVF success rates. This novel research project has the potential to change the future of embryo screening in New Zealand and internationally.

 

EFFECTIVENESS OF FOOTWEAR IN PEOPLE WITH GOUT – 5114003 ($106,553 – 2 years)

Prof Keith Rome, A/Prof Nicola Dalbeth, Prof Peter Gow, Prof Peter McNair, A/Prof Alain Vandal
Dept of Podiatry, Auckland University of Technology

Gout is a major cause of musculoskeletal disability in Aotearoa New Zealand. Foot pain occurs in most people with gout. There is strong evidence that many people with gout wear inappropriate or poor quality footwear, and that ill-fitting footwear may contribute to further foot problems. We have shown in a recent feasibility study that footwear with good cushioning, motion control and adequate width reduces foot pain and disability in the short term. We propose a long-term randomised controlled trial examining the effects of a footwear intervention on foot pain and disability. The trial will assess the effect of standard podiatric care and a relevant footwear intervention against standard podiatric care only. The study findings will be used to make evidence-based recommendations regarding footwear intervention for people with gout.

 

THE ROLE OF INTRACELLULAR AGEs IN THE DIABETIC HEART – 1114004 ($159,335 – 2 years)

Dr Kimberley Mellor, Prof Margaret Brimble, Prof Lea Delbridge
Dept of Physiology, University of Auckland

In New Zealand, more than 200,000 people are currently diagnosed with diabetes and the burden falls disproportionately on the Maori and Pacific Island populations, with the prevalence and death rates approaching double those of Pakeha. Diabetic patients have 2.5-fold increased risk of heart failure. The prevalence of diastolic dysfunction in type 1 and type 2 diabetes is estimated to be as high as 40-75% without overt coronary artery disease. The myocardial origins of this vulnerability are poorly understood and effective treatment strategies are lacking. This study aims to establish that in diabetes – glycation of intracellular proteins in the heart is a pathology to target therapeutically. In characterising intracellular glycation as a novel component of diabetic cardiomyopathy, this project has potential to contribute a highly significant advance in knowledge in this field – and to prompt an innovative paradigm shift in thinking about causation of diabetic cardiopathology. It is anticipated that this research will translate into specific fundamental outcomes relating to the science and the treatment of heart failure in diabetic patients.

 

PROTEOMIC PROFILING OF PRODRUG-ACTIVATING ENZYMES IN LEUKAEMIAS – 1114005 ($158,973 – 2 years)

Dr Yongchuan Gu, Prof Peter Browett, Dr Frederik Pruijn, Prof William Wilson
Auckland Cancer Society Research Centre, University of Auckland

The anticancer prodrug PR-104, developed in the University of Auckland, was designed to be activated by reductase enzymes in tumours under conditions of low oxygen (hypoxia), which is a hallmark of tumours. During its evaluation in clinical trials with solid tumours, pre-clinical research identified a reductase, AKR1C3, which also activates PR-104 in the presence of oxygen. AKR1C3 is highly expressed in some leukaemias. Given that the bone marrow becomes hypoxic in advanced leukaemias, it was suggested that PR-104 might exploit both AKR1C3 and hypoxia, leading to a phase I/II trial of PR-104 in relapsed acute myeloid and lymphocytic leukaemias. The trial showed good although variable responses, but only limited evaluation of biomarkers was undertaken. We will develop a targeted proteomics assay for PR-104 reductases, using a powerful mass spectrometry approach that allows simultaneous quantification of large numbers of proteins in clinical samples. The assay will be optimised for bone marrow and blood samples from patients and its ability to predict metabolic activation of PR-104 will be evaluated. If successful, the assay will be used in subsequent trials of PR-104 in human leukaemias to assess its role in identifying responsive patients in a personalised medicine context.

 

MODEL-BASED LVD ASSESSMENT – 1114006 ($125,014 – 2 years)

Dr Avan Suinesiaputra, Prof Alistair Young, A/Prof Brett Cowan
Dept of Anatomy with Radiology, University of Auckland

Ventricular dyssynchrony is the main predictor for cardiac resynchronisation therapy (CRT), an invasive procedure that can dramatically improve the morbidity and mortality of patients with chronic heart failure. However, 30% of patients who undergo CRT do not receive any benefit due to the lack of appropriate selection criteria, including current assessment technique. We aim to develop a more accurate and reproducible left ventricular dyssynchrony (LVD) assessment method based on mathematical modelling of the left ventricle derived from cardiac MRI. We are also investigating a novel prognostic prediction method based on multi-dimensional analysis of shape, motion and auxiliary diagnostic information, such as scar tissue location and electrical timing. This project will provide a valuable clinical tool to assess ventricular dyssynchrony prior to CRT procedure.

 

SELECTIVE INHIBITORS OF MRSA PYRUVATE KINASE AS STRUCTURALLY UNIQUE, NEXT-GENERATION ANTIBIOTICS – 1114007 ($12,000 – 2 years)

Dr Jonathan Sperry
School of Chemical Sciences, University of Auckland

This research will have implications in the treatment of infections caused by antibiotic resistant bacteria. Successful collaborative efforts with The University of British Columbia (UBC) have identified a small molecule inhibitor of methicillin-resistant staphylococcus aureus (MRSA) pyruvate kinase (PK) that exerts this inhibitory activity selectively over human isoforms. We will use these preliminary results to guide the rational design of a focused compound library, which will be sent to UBC for further biological analysis against MRSA PK. By conducting several iterations of this synthesis/biological evaluation process, we will develop potent, selective inhibitors of MRSA PK well-suited for in vivo evaluation as structurally unique antibiotics that work on a novel biological target compared to existing therapies.

 

WHY ARE KNEE LIGAMENT SURGERIES FAILING IN YOUNG PEOPLE? – 1114008 ($159,171 – 2 years)

Dr David Musson, Mr Brendan Coleman, Prof Jillian Cornish, Dr Dorit Naot, Dr Matthew Street
Dept of Medicine, University of Auckland

Tears of the anterior cruciate ligament, an important stabiliser of the knee joint, are a significant clinical problem in active, young individuals, with surgeries costing over $18 million per year in New Zealand. Recent data has highlighted that patients under the age of 20 undergoing surgical reconstruction of their anterior cruciate ligament are more prone to re-tearing. This study aims to understand the biological mechanisms behind this phenomenon by comparing the mechanical strength, structure and gene expression profile of biopsies from patients under the age of 20 and biopsies from those over the age of 20 undergoing anterior cruciate ligament reconstruction.

 

TARGETING THE MECHANISM OF HOST RECOGNITION TO PREVENT BACTERIAL INFECTIONS – 4114009 ($53,580 – 1 year)

Dr Xue-Xian Zhang, A/Prof John Harrison, Dist. Prof Paul Rainey, Dr Stephen Ritchie
Institute of Natural and Mathematical Sciences, Massey University

With the widespread increase of bacterial resistance to antibiotics, new strategies to prevent and treat healthcare-associated infection are urgently required. This proposal addresses a crucial gap in our current understanding of how bacteria cause disease – namely, how pathogenic bacteria recognise vulnerable hosts for successful colonisation and immune evasion. To date, our research has focused on Pseudomonas aeruginosa, an environmental pathogen that causes a wide range of healthcare-associated infections and pulmonary infections in people with chronic lung diseases, particularly cystic fibrosis. Recent progress has led us to a novel hypothesis that P. aeruginosa recognises urocanate in human tissues and use it as a trigger for bacterial invasion. To test this hypothesis, we will develop the analytic techniques that are essentially required for the detection of urocanate in chemically complex human samples (e.g., sputum, urine and wound fluid). Next, we will screen ~200 specimens from patients with various diseases (including asthma, diabetes and cystic fibrosis) in order to identify the urocanate-containing tissues for further investigation into the association between urocanate concentration and predisposition to bacterial infection. The data will form the basis for the development of new strategies to prevent bacterial infection through interrupting the urocanate-mediated host recognition.

More Awarded Project grants
Awarded Project Grants 2019
Awarded Project Grants 2018
Project Grants Awarded 2017
Image courtesy of Ponsulak / FreeDigitalPhotos.netProject grants awarded 2016
Project grants awarded 2015
Project grants awarded 2013