AMRF awards over $1.13million to Auckland researchers in its latest grant round

13 July 2011

The Auckland Medical Research Foundation (AMRF) announced Wednesday July 13 that it has approved $1,132,631 in funding to medical researchers in Auckland in its June 2011 grant round.

Foundation Executive Director Kim McWilliams says, “From our beginnings, we have promoted research of high scientific value and purpose across the full spectrum of medical science. Many of these researchers already have and will go on to become leaders and internationally recognised in their particular discipline or field of medicine. This round again saw applications rise to record levels, so many worthy projects were not able to be funded. This is what drives us to build our income to meet this demand.”

The grants included 10 successful research projects ($930,931), the Ruth Spencer Medical Research Fellowship ($178,000) to Dr Primal Singh, and 10 travel grants ($23,700) for researchers to present their research overseas. Research grants were awarded over a variety of research areas ranging from kidney disease, brain research and autism, stem cells, cancer, diabetes, vaccine development, heart failure, and bone health.

The AMRF is a major independent funding agency and Charitable Trust that provides contestable funding for medical research based in the greater Auckland region. Over the past 55 years the AMRF has distributed over $40 million in funding to a wide range of research activities - $3.3million distributed in 2010 alone.

Details of the 2011 AMRF Grant Round: PGAF AND RENAL DISEASE ($140,000 - 2 YEARS ) A/Prof Alan Davidson , Dept of Molecular Medicine & Pathology, The University of Auckland

New Zealand has alarmingly high rates of chronic kidney disease, particularly amongst the Maori and Pacific peoples where diseases such as diabetes and hypertension damage the blood filters in the kidney. We have identified a new protein, called PGAF that plays a critical role in maintaining the integrity of the kidney’s blood filters. By understanding how PGAF functions we hope to develop new therapies to preserve kidney function in patients with chronic kidney disease.

VACCINATION AGAINST GAS ($11,380 - 1 YEAR) Dr Fiona Radcliff, A/Prof Thomas Proft, Prof John Fraser , Dept of Molecular Medicine & Pathology, The University of Auckland

Streptococcus pyogenes, or Group A streptococcus (GAS), is an important human pathogen responsible for a wide range of diseases from minor throat infections to life threatening flesh-eating disease. There is no vaccine available for GAS and several promising candidates have failed to reach the clinic because of cross-reactivity with human tissue. We have identified a virulence factor, SpnA, which is expressed in all clinical isolates and is associated with pathogen survival in human blood. Patients do develop specific immune responses (antibodies) which can inhibit the activity of SpnA, but this response is generally transient and present immediately after infection. We aim to test whether we can elicit a robust and durable antibody response to SpnA by combining it with an in-house vaccine carrier, M1. The M1 carrier targets immune cells called antigen-presenting cells, leading to improved delivery of vaccine candidates and enhanced immune responses. Vaccine preparations will be tested in mice and if this approach shows potential, the mice will be infected with GAS to determine whether vaccination to SpnA stimulates protective immunity. These studies will enable us to test the potential of a novel vaccine candidate for GAS, a significant human pathogen.

DIABETES CVD RISK EQUATION VALIDATION ($69,854 - 1 YEAR) A/Prof Carolyn (Raina) Elley, Mrs Elizabeth Robinson, A/Prof Tim Kenealy, Dr Sue Wells, Dr Paul Drury, Prof Bruce Arroll, Dept of General Practice & Primary Health Care, The University of Auckland

People with diabetes are at increased risk of having a heart attack or stroke. This risk can be calculated for each person, depending on their demographic and health characteristics, and used to help decide on the best treatment. Current risk calculation, however, is based on findings from a US study conducted more than 50 years ago. We have developed and published a new risk equation, using recent New Zealand data. The new equation suggests that we are currently under-treating certain groups in New Zealand (NZ), including people with poorly controlled diabetes or kidney impairment, especially for Maori, Pacific and Indian populations. This proposal aims to validate the new risk equation using clinical data from general practices in NZ to ensure it is more accurate than the US equation. We also propose to develop and test a new open-access web-based risk calculator based on the new NZ risk equation.

INDUCED NEURAL PRECURSOR CELLS ($144,023 - 2 YEARS) Dr Bronwen Connor, Dr Christof Maucksch, Dr Mirella Dottori, A/Prof Cris Print ,  Dept of Pharmacology, The University of Auckland

It has long been considered that once a cell reaches maturity it is unable to change to a different cell type. However, recent advances in stem cell biology have shown that mature cells, such as skin cells, can be transformed back to an "embryonic-like" stem cell state where cells exhibit pluripotency (the ability to become any cell type) by the forced expression of specific genes (reprogramming). Advancing this capability, we propose it is possible to convert one cell type to another directly, without the need to first revert the cell to a pluripotent stem cell state. This project aims to establish an innovative approach for generating immature brain cells (neural precursor cells) directly from adult human skin. Of major significance is that this will avoid the need to generate an intermediate embryonic stem cell phase, providing neural precursor cells for research and therapeutic applications without risk of tumour formation from pluripotent stem cell contamination. This project will establish cell reprogramming as a key capability in New Zealand. The ability to directly generate human neural precursor cells offers a powerful system for studying brain development, modeling neurological disease, drug discovery and eventually, cell replacement therapy.

ADRENOMEDULLIN RECEPTOR ANTAGONISTS ($129,957 - 2 YEARS) A/Prof Michael Hay, Dr Debbie Hay, Dr Jack Flanagan , Auckland Cancer Society Research Centre, The University of Auckland

One of the hallmarks of cancer is increased formation of blood vessels (angiogenesis) and this process is mediated, in part, by a hormone known as adrenomedullin (AM). Inhibition of angiogenesis has been clinically proven to stop tumour growth, thus new approaches to reduce angiogenesis have potential as an anticancer therapies. This project seeks to design and synthesize new agents that selectively inhibit the ability of AM to promote angiogenesis by blocking the cellular target of this hormone. This target, known as the AM receptor, is found on the surface of cells. AM acts through this receptor to stimulate signalling and promote blood vessel growth. The receptor is made of two subunits; between these is a groove, where AM binds to produce its effects. We will use medicinal chemistry, combined with molecular modelling, to create new molecules that block the access of AM to this groove and therefore reduce its activity in blood vessels. These molecules will be tested for their ability to selectively bind to the AM receptor and to stop AM signalling. This project represents the first steps towards identifying a new targeted anticancer therapy.

THE SYNAPTIC BASIS OF AUTISM ($68,265 - 1 YEAR) (Co-funded with Neurological Foundation $136,531 total) Dr Johanna Montgomery, Prof Craig Garner , Dept of Physiology & Centre for Brain Research, The University of Auckland

Autism Spectrum Disorders are complex disorders that are diagnosed based on behavioural symptoms including social and cognitive impairments, communication difficulties and repetitive behaviours. Interestingly, many of the genes that have been implicated in Autism encode proteins found at excitatory synapses in the brain. In this research proposal we will form an international collaborative research effort to test the hypothesis that the Autism-associated mutations in these synaptic proteins disrupt the function of synapses. Using electrophysiology recordings as a measure of synapse function, we will compare how proteins that are associated with Autism can alter synapses in the hippocampus, the part of the brain critical for cognitive functions such as learning and memory. We will also begin to determine the mechanisms underlying how these changes occur. These experiments have the potential to determine how the formation, plasticity and maturation of excitatory synapses may be disrupted in Autism, leading to interference with cognitive function and behaviour.

CB2 IN THE BRAIN ($74,457 - 1 YEAR) Prof Michelle Glass, Dr Scott Graham , Dept of Pharmacology & Clinical 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 are 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. This study aims to optimise a sensitive method which will allow for the determination of CB2 gene expression in the normal healthy human brain.

FLUORIDE FOR BONE HEALTH ($30,738 - 6 MONTHS) A/Prof Andrew Grey , Dept of Medicine, The University of Auckland

Low dose fluoride has potential to become a treatment for osteoporosis, which is a major public health problem. We have almost completed a placebo-controlled randomized clinical trial of low-dose fluoride in 180 postmenopausal women with osteopenia (thin bones), funded by the Auckland Medical Research Foundation. The current proposal requests working expenses to conduct important efficacy and safety analyses from this trial.

GLYCOSYLATED PROTEINS IN HUMAN HEART FAILURE ($131,768 – 2 YEARS) Dr David Crossman, Dr Mia Jullig, Dr Peter Ruygrok, A/Prof Christian Soeller, Prof Mark Cannell, Dept of Physiology, The University of Auckland

Human heart failure is the inability of the heart to pump enough blood to meet the energetic demands of the body. This is a serious health condition that is incapacitating to the patient and will eventually require heart transplantation but this is only available to a few patients due to the low numbers of donor hearts that become available. This disease is a serious burden on New Zealand society and is an area of medical research with the potential to improve the lives of many. We have previously discovered that glycosylation or sugar modifications of proteins increase in heart failure and may have serious impact on electrical signalling and force generation in cardiac muscle. In this study we will identify which glycoproteins have changed with proteomic finger printing. This technique works by shattering proteins into fragments or peptides and accurately measuring their size with mass spectrometry. This size information is then used to positively indentify proteins from a database of all know proteins. The cellular location and structure of identified glycoproteins will then be imaged using fluorescent microscopy. It is hoped the research will help identify new avenues for future heart failure therapies.

HEALING WITH HOLOCLONES ($130,489 - 2 YEARS) A/Prof Trevor Sherwin , Dept of Ophthalmology, The University of Auckland The cornea is the front transparent surface of the eye. Its transparency is crucial for light entering the eye and for the focusing of light onto the photoreceptors in the retina. Specialised adult stem cells that are abundant at the limbus, have important functions within the retention of normal corneal integrity and repair upon injury. Limbal stem cell deficiency (LCSD) leads to vision impairing disabilities which severely affect the patient’s independence and quality of life. Treatment for LSCD patients has long been frustrating with many patients having a poor prognosis. Recent advances in therapeutic options for LSCD patients use an autologous graft of the patients’ own limbal cells following expansion in the laboratory. However this form of autologous transplant is highly undefined and has varying levels of success. This study proposes a new unit of tissue for transplantation that will provide a highly defined transplantable entity for implantation at a defined site (the limbus) that may have the potential to restore the limbus to near pre-LSCD condition. Achievement of this will not only correct the current defect for the patients but may also provide the eye with restored long term ability to heal itself.

RUTH SPENCER MEDICAL RESEARCH FELLOWSHIP The Ruth Spencer Medical Research Fellowship was awarded to Dr Primal Singh from the Department of Surgery at the University of Auckland ($178,000). This prestigious award is to encourage medical or science graduates with exceptional potential to undertake fulltime research for a PhD or an MD. Dr Singh is an outstanding young medical doctor who will develop his research skills by investigating the effects of a class of drugs, the statins, on the body?s stress response to surgery, with the aim of reducing post-surgical complications and improving patient recovery.

PERIOPERATIVE USE OF STATINS TO REDUCE MORBIDITY AFTER COLORECTAL SURGERY ($178,000 - 2 YEARS) Dr Primal Singh , Dept of Surgery, South Auckland Clinical School, The University of Auckland With New Zealand having one of the highest incidence rates of colorectal cancer in the developed world, colorectal surgery is among the most common major operations performed in the country. Although surgery can provide a cure for colorectal cancer, it has a high risk of developing serious complications which leads to significant distress for the patient and often a prolonged stay in hospital. The body’s response to surgery, which involves inflammation and hormonal changes, increases the risk of developing such complications and reducing this ‘stress response’ is shown to be beneficial. Statins are a widely used class of cholesterol-lowering medication that have additional benefits such as decreasing inflammation and improving the body’s response to injury and infection. Increasing evidence suggests these effects may reduce the body’s stress response to surgery and therefore decrease the risk of complications developing after surgery. We aim to explore these benefits of statins by conducting a study that investigates their use in patients undergoing colorectal surgery. If statin use can decrease the morbidity associated with colorectal surgery, it would significantly improve patient care and lead to better health outcomes.

For further information please contact: Kim McWilliams Executive Director Auckland Medical Research Foundation 09 923 1701 021 339 520 kim.mcwilliams@medicalresearch.co.nz