Over $1.4m awarded to Medical Researchers

Media Release

August 2013

Auckland Medical Research Foundation Awards over $1.4m to Medical Researchers

The Auckland Medical Research Foundation (AMRF) has recently announced $1,413,701 in funding to medical researchers in the first three funding rounds for 2013.

Foundation Executive Director, Kim McWilliams says, “More research is the only way we can ensure genuine advances in medicine and outcomes for patients. From our beginnings, we have promoted research of high scientific value and purpose across the full spectrum of medical science. This round again saw applications rise to record numbers, and we are pleased to see the broad reach of successful grants”.

The successful grants included 14 research projects ($1,315,799), 34 travel grants ($84,959) for researchers to present their research overseas and 1 Gavin and Ann Kellaway Medical Research Fellowship ($12,943). Project grants were awarded over a variety of research areas ranging from Cell Biology; Reproduction, Maternal and Newborn Health; Diabetic Cataracts; Respiratory Infections and Malaria; Neuroscience; and Acute Pancreatitis.

See Below for Project Summaries

The Auckland Medical Research Foundation is a major independent funding agency and charitable trust that provides contestable funding for medical research across the complete spectrum of modern medicine. Over the last 57 years we have distributed over $47 million in funding to a wide range of research activities – currently around $3 million annually.

Our Foundation is unique in the charity sector, in that every dollar donated from within the community goes directly and fully (100%) to research. Our administration costs are generously supported by a benefactor.

For further information on the current grants awarded and application forms for future grant rounds see our website at www.medicalresearch.org.nz

ENDS
PROJECT GRANTS AWARDED JULY 2013

GENETICS OF ANTERIOR CORNEAL DYSTROPHY 1113001 ($138,968 – 18 months)

Dr Andrea Vincent, A/Prof Trevor Sherwin, Prof Phil Crosier

Dept of Ophthalmology, The University of Auckland

Inherited disorders affecting the clear front window of the eye are known as corneal

dystrophies. Members of a unique NZ family have significant recurrent episodes of eye pain from childhood, caused by the front surface of the cornea falling off, which often leads to progressive scarring. The cause of this rare disease is unknown, however our recent work shows this disease is due to one of two gene mutations on chromosome 10. Our aim is to understand the normal role of these genes, and the consequence of changes to these genes, in corneal health and disease. We will look at the two protein products of these genes in donor corneas to establish where the proteins sit within the outer-most layer of corneal cells, and what stimuli, e.g. stress or trauma, may change their production. We will then establish disease models in zebrafish by introducing the disease gene(s) into the developing zebrafish embryo, to see the effect on the zebrafish cornea. Using this animal model of a rare genetic disorder will help identify an underlying cause for a more common condition, recurrent corneal erosion, and will help target effective treatments for corneal wound healing, both accidental, and due to surgical interventions.

DANGEROUS DEBRIS 1113002 ($139,447 – 18 months)

A/Prof Larry Chamley, Dr Qi Chen

Dept of Obstetrics & Gynaecology, The University of Auckland

Preeclampsia affects approximately 3000 New Zealand women and their babies annually. Preeclampsia causes potentially life-threatening high blood pressure in the mother and often requires the premature delivery of the baby to prevent the death of the mother or baby. Something from the placenta triggers preeclampsia but we do not know exactly what this is. We have evidence that dead cells from the placenta called syncytial nuclear aggregates may be this trigger but only if they died by a process called necrosis. We also have evidence that antiphospholipid autoantibodies, that are found in some women with preeclampsia, cause syncytial nuclear aggregates to die by necrosis. Why death by necrosis is so important in developing preeclampsia is unclear but this may be because necrotic syncytial nuclear aggregates display molecules called danger signals which cause mum’s blood vessels to tighten leading to the high blood pressure of preeclampsia. We will investigate whether antiphospholipid antibodies cause syncytial nuclear aggregates to display danger signals and whether syncytial nuclear aggregates from preeclamptic pregnancies display danger signals. Ultimately our goal is to understand how necrotic syncytial nuclear aggregates affect blood vessels and armed with that knowledge, we hope to improve treatments for women affected by preeclampsia.

TARGETING REPLICATION OF A HUMAN RESPIRATORY VIRUS 1113003 ($139,620 – 2 years)

Dr Esther Bulloch, Dr Richard Kingston

School of Biological Sciences, The University of Auckland

Respiratory Syncytial Virus (RSV) is the primary cause of serious respiratory disease in infants. The reported rates of RSV infection in New Zealand are almost twice that of Europe and the USA, and are particularly high for the Maori and Pacific Island population. There is no vaccine that prevents RSV infection, nor any effective therapy to treat infected individuals. We seek to understand how RSV replicates within human cells. RSV has complex replication machinery that creates the blueprint for new viral proteins, messenger RNA (mRNA), as well as copying the entire viral genome. However, the virus lacks a protein production system for

translating viral mRNA into viral proteins, so it co-opts the system of the human host cell. For the viral mRNA to be processed by the host cell it must have specific chemical modifications. RSV and related viruses have unusual enzymes integrated into their replication machinery that carry out these mRNA modifications. We will isolate these enzymes using a technology developed in our laboratory, and carry out the first detailed molecular studies of their activity. The long-term goal is to develop new anti- viral agents that prevent RSV replication by targeting its unique mRNA modifying enzymes.

ANTIMALARIAL CONJUGATES 1113004 ($23,600 – 2 years)

A/Prof Brent Copp, Dr A Norrie Pearce

School of Chemical Sciences, The University of Auckland

Malaria is a parasitic disease that has re-emerged as a growing human health hazard in the past few decades, affecting millions of people in Africa, Asia and South America. The drugs that are available for the treatment of malaria are becoming increasingly inadequate because of resistance and lack of patient compliance for multidrug treatment regimes. New, more efficient medications are urgently needed. We have recently discovered a class of natural products that exhibit moderate antimalarial activity and which when synthesised and modified in certain ways yield drug candidates that effectively kill malaria in mammals. This project involves the synthesis and biological evaluation of new molecules based around our discovery, where we will optimize the parasite killing power of our current antimalarial while at the same time reducing the cost of its large scale manufacture. Our so-called multimodal antimalarials will provide proof of concept of combining therapeutics that kill and prevent reinfection with malaria into a single drug compound that not only is effective at disease treatment but also avoids resistance mechanisms and enhances patient compliance.

TROPHOBLAST STEM CELLS 1113005 ($50,000 – 18 months)

Dr Jo James, A/Prof Larry Chamley

Dept of Obstetrics & Gynaecology, The University of Auckland

The placenta is the baby’s life-support system in utero, and its formation and function in early pregnancy is crucial for pregnancy success. Inadequate placental development results in pregnancy disorders from conception to birth including miscarriage, preeclampsia (high blood pressure in pregnancy) and intrauterine growth restriction (small babies), which together affect around 15,000 pregnancies in NZ each year. Despite its importance, we understand very little about how it the human placenta develops. This research aims to address this problem by studying the stem cells from which the placenta is formed. The placenta is composed of specialised cells called trophoblasts, which form different populations each critical for pregnancy success, but we do not understand how these populations arise. We have isolated cells that are likely to be trophoblast stem cells from early placental samples, and are characterising these cells in order to develop trophoblast stem cells for use in the laboratory. This will allow us to study what regulates the formation of different trophoblast populations. This research will help us identify potential underlying causes of pregnancy disorders and may lead to new therapies for pregnancies with poor placentas.

DIABETIC CATARACT 1113006 ($59,061 – 18 months)

Prof Paul Donaldson, Ms Irene Vorontsova

School of Medical Sciences, The University of Auckland

Cataract occurs earlier in patients with diabetes, and is associated with a higher rate of surgical complications. Due to the increasing incidence of diabetes, a cataract epidemic is looming that will place an economic burden on the health system. Research efforts to alleviate this burden have focused on finding alternative medical therapies to delay cataract

progression and reduce the need for surgery. The Molecular Vision Laboratory at the University of Auckland has shown that dysfunction in the ability of lens to regulate cell volume is an underlying cause of diabetic cataract. On-going work by the Auckland group has identified the key membrane transport proteins that effect changes in lens cell volume. More recently a PhD student in the laboratory, Irene Vorontsova, has identified the regulatory machinery that modulates the activity of these transporters and which therefore ultimately determine the transparency of the lens. Ms Vorontsova is a former recipient of the AMRF’s Senior Scholarship and in this current application funds are requested to continue Ms Vorontsova’s work into how these regulatory pathways are disrupted in the diabetic lens. This work will determine whether these regulatory pathways are potential targets for development of therapies to combat the diabetic cataract epidemic.

EFFECTS OF PARKINSONIAN TOXINS ON THE LOCUS COERULEUS 1113007 ($103,000 – 2 years)

Prof Janusz Lipski, Mr Andrew Yee, Dr Peter Freestone, Dr Ji-Zhong Bai

Dept of Physiology & Centre for Brain Research, The University of Auckland

Parkinson's disease (PD) is one of the most common degenerative brain disorders leading to motor deficits such as tremor in hands, slowness of movement, muscle stiffness and gait disturbance. Importantly, PD patients also suffer from debilitating non-motor symptoms, such as sleep disturbance, cognitive and mood disorders and dysfunction of the cardiovascular system, bowel and bladder, which cause additional disability and severely impact the quality of life of those affected with PD. Previous research indicates that at least some of these non-motor symptoms are due to degeneration of nerve cells in the Locus Coeruleus (LC), but the cellular mechanism of this damage is not known. Remarkably, degeneration of the LC can exceed damage of the Substantia Nigra pars compacta (SNc) associated with the ‘classical’ motor symptoms of the disease. Our study, conducted on isolated animal brain tissue, will test and compare the effects on LC neurons of two environmental toxins/pesticides which have been implicated in the pathogenesis of some cases of PD: rotenone and MPP+. We will also compare the effects evoked in LC neurons with the responses induced in SNc neurons, and a further group of neurons which is not affected in PD. This research will advance our understanding of the mechanisms of action of parkinsonian toxins on neurons vulnerable in PD, and should help to elucidate the complex relationship between the motor and non-motor symptoms in this debilitating disorder.

THE TUI STUDY 1113008 ($78,500 – 2 years)

Prof Cindy Farquhar, Dr Emliy Liu, Ms Nicola Arroll

Dept of Obstetrics & Gynaecology, The University of Auckland

Up to 20% of New Zealanders will experience infertility at some point in their lives. The TUI study aims to evaluate the effectiveness of a fertility treatment called intrauterine insemination (IUI) with stimulation. IUI is especially popular in New Zealand as couples with unexplained infertility cannot access the publicly funded fertility clinics unless they have been infertile for five years. As a result many women decide to pay for one to two cycles of stimulated IUI while they are waiting to meet the criteria for public funding. IUI with ovarian stimulation involves the women taking medication to stimulate ovulation before introducing sperm directly into the uterus in the hope of aiding conception. Currently knowledge around the effectiveness of this treatment in women with unexplained infertility and low chance of pregnancy (less than 30% chance) is not extensive. If this randomised controlled trial demonstrates that intrauterine insemination with stimulation is effective then this would provide evidence for a less invasive and cost effective alternative to In vitro fertilisation for women with unexplained infertility.

HOMING IN ON THE EPITOPE TARGETS FOR NR1 ANTIBODIES 1113009 ($138,076 – 2 years)

A/Prof, Deborah Young

Dept of Pharmacology, & Clinical Pharmacology, The University of Auckland

The NMDA receptor in the brain plays an important role in functions such as learning and memory. Over-activation or dysfunction of the NMDA receptor that occurs in certain neurological diseases causes neuronal cell death or can affect learning and memory making this receptor a key target for therapies. Traditional NMDA receptor blockers that aim to prevent the deleterious effects associated with NMDA receptor dysfunction are associated with adverse side-effects in humans which limits their usefulness. We have shown that antibodies to the NR1 subunit of the NMDA receptors can alter the function of NMDA receptors leading to improved learning and memory, and resistance to experimentally-induced brain insults in rats. Anti-NMDA receptor encephalitis, a disease associated with seizures and memory loss in humans is mediated by NR1 antibodies that could be binding to a region of the NR1 protein that is different to our cognitive-enhancing and protective NR1 antibodies. Here, we use rat models to help distinguish the parts of the NR1 subunit important for generating NR1 antibodies that produce beneficial and detrimental effects on cognition and neuroprotection. These results will contribute to the development of a new class of safe therapies applicable for a broad range of neurological conditions.

Gcn2 INTERACTOME 4113010 ($66,630 – 4113010)

Dr Evelyn Sattlegger, Ms Su Jung Lee

Institute of Natural and Mathematical Sciences, Massey University

The enzyme Gcn2 is involved in many life-affirming biological functions, such as proper food selection, viral defence, memory, and overcoming stress and starvation. Consequently, Gcn2 is a highly relevant protein, for medicine especially as research has linked Gcn2 to various diseases/disorders such as aberrant feeding behaviour, Alzheimer’s, cancer, and impaired viral defence. Given that these diseases/disorders significantly impact on health and quality of life, this underscores the need to find drugs for their treatment. However, in order to prevent unwanted side effects, measures are necessary that only treat the specific Gcn2 function that went awry. For this we first need to fully understand how Gcn2 is kept in check in the cell. Although Gcn2 is a topic of research world-wide, there remains one significant knowledge gap central to understanding Gcn2 function: the comprehensive identification of proteins that bind to Gcn2, and thereby control Gcn2. These proteins are promising targets for pharmaceutical treatments to modify specific Gcn2 functions that lead to a particular Gcn2-associated disease/disorder. The PI’s research team is in a unique position to identify these Gcn2 binding proteins, and to spearhead the first characterisation of these proteins, as the relevant experimental procedures have been established in her lab.

CB2 IN THE DISEASED HUMAN BRAIN 1113011 ($66,792 – 1113011)

A/Prof Michelle Glass, Dr Scott Graham

Dept of Pharmacology, The University of Auckland

Cannabinoid CB2 receptors have been suggested to be an appealing target for neuroinflammatory disorders as many believe them to be found only on immune cells. However, their distribution is actually highly controversial with some groups reporting wide spread neuronal distribution, while others see little evidence for CB2 in the brain. Part of the reason for these discrepancies is that the antibodies used to detect this protein are not entirely specific. Furthermore, many of the assumptions about CB2 expression in the brain are based on animal studies and may not represent the situation in the human brain. As many drug companies are aiming to bring CB2 directed therapies onto the market it is critical that the localisation of the receptor be accurately determined. We have recently developed a

sensitive method for determining the expression of CB2 in the normal healthy brain, which we now wish to apply to disease brains from the Human Brain Bank.

ORAL DEXTROSE GEL FOR PREVENTION OF HYPOGLYCAEMIA IN AT RISK NEWBORN INFANTS 1113012 ($140,672 – 2 years)

Dr Jane Alsweiler, Professor Jane Harding, Dr Jo Hegarty

Dept of Paediatrics: Child and Youth Health, The University of Auckland

Hypoglycaemia (low blood sugar) is the commonest metabolic condition in newborn babies, affecting up to 30% of babies born in Auckland hospitals. It frequently leads to neonatal intensive care unit admission and may cause long-term brain damage. Infants of diabetic mothers are particularly at riskrates of maternal diabetes have quadrupled in NZ over the last two decades from 2% to 8%, with Polynesian and Maori women having the highest rates. There currently are no evidence-based strategies to prevent hypoglycaemia and its adverse consequences. We have shown that oral dextrose gel is effective in reversing established hypoglycaemia, halving NICU admission rates and improving rates of breastfeeding at two weeks. We now propose a trial investigating the effectiveness of dextrose gel for prevention of hypoglycaemia and its consequences in at risk babies. We will compare two different doses of dextrose gel, given on one or more occasions at feed times to those newborn babies at increased risk of having hypoglycaemia to determine a dose that will best prevent neonatal hypoglycaemia. We will determine whether dextrose gel prevents this common newborn condition with potential long-term health consequences. Such an intervention would revolutionise management of neonatal hypoglycaemia around the world.

GAVIN AND ANN KELLAWAY MEDICAL RESEARCH FELLOWSHIP

Dr Bruce Russell

School of Pharmacy, The University of Auckland

To build on existing and establish new collaborations in the United Kingdom and USA and attend conferences in Germany.

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