CBR scientists boosted with support from AMRF

The Auckland Medical Research Foundation has announced its latest round of grants, with several innovative projects funded in the Centre for Brain Research. The research will help to develop new treatments for Huntington’s disease, obesity, visual defects, and hearing loss.

THE SYNAPTIC BASIS OF HUNTINGTON’S DISEASE
– $141,154
Dr Johanna Montgomery, Dr Ailsa McGregor Dept of Physiology & Centre for Brain Research, The University of Auckland

All neurodegenerative diseases have direct or indirect effects on synapses in the brain. Therefore a major step towards understanding what goes wrong in the diseased brain is to understand how synapse function is altered by disease. In this proposal we seek to determine the source of synapse dysfunction in Huntington’s Disease (HD). Previous work on HD mouse models has shown that receptors on the surface of neurons are mis-localised, inducing changes in synapse function. Here we will focus on two synaptic proteins, bSAP97 and aSAP97, which we have recently shown can control the distribution of receptors on neurons (Li et al., 2011, J. Physiology 589, 4491-4510). We will utilise a cellular and an animal model of HD to determine whether changing the expression levels of bSAP97 or aSAP97 can rescue normal receptor distribution, and whether this subsequently rescues normal synapse function. These cellular data will identify whether a and/or bSAP97 are part of the pathological signature for HD and also whether they could be potential therapeutic targets.

THE EFFECT OF NEONATAL HYPOGLYCAEMIA ON VISUAL DEVELOPMENT
– $97,250 Mr Nabin Paudel
Dept of Optometry & Vision Sciences, The University of Auckland

Newborn babies commonly experience low blood sugar, a condition known as neonatal hypoglycaemia.  As glucose is the brain’s main energy source, this condition may impair neurological function, however, at present, very little is known about the effect of neonatal hypoglycaemia on brain development.  As a consequence, the level of neonatal hypoglycaemia that requires treatment in early infancy is currently unknown.  This PhD project forms part of a large multidisciplinary study known as the Children with Hypoglycemia and their Later Development (the CHYLD study) which aims to assess the developmental effects of neonatal hypoglycaemia in a cohort of 500 children whose blood glucose levels were measured continuously for several days after birth.  The aim of this specific project is to assess visual function in these children at the ages of 2 and 4.5 years.  Vision is of particular interest as neonatal hypoglycaemia may preferentially affect visual brain areas.  The assessments include a range of vision tests targeting specific regions of the visual cortex and will therefore provide new insights into the effect of neonatal hypoglycaemia on the rate and extent of visual cortex development.  The study will also provide important information regarding the treatment and management of hypoglycaemia in newborns.

MELANOCORTIN TREATMENT FOR OBESITY
– $166,636
Dr Kathy Mountjoy, Dr Ailsa McGregor Dept of Physiology, The University of Auckland

Stress, weight gain and glucose metabolism are influenced by a group of hormones called melanocortin peptides. These peptides comprise chains of amino acids, of varying length, and are derived from one large precursor protein found in the brain and pituitary gland, called proopiomelanocortin (POMC). Special enzymes chop-up POMC to form the melanocortin peptides, according to the body’s requirement. We have developed a mouse that lacks a particular 13 amino acid melanocortin peptide called adrenocorticotropic hormone (ACTH1-13). These mice can be used to study what effects of ACTH1-13 on physiological function. The mice appear normal until they reach puberty and then they develop obesity, but not diabetes. Treatment of these obese mice with ACTH1-13 or a natural variant that is slightly chemically altered, called -melanocyte stimulating hormone (-MSH), reduced mouse body weight and fat mass when mice were fed a normal diet. In light of the worldwide obesogenic environment, we will now test whether obesity and diabetes in these mice is exacerbated by a feeding a high-fat diet, and whether melanocortin hormone treatment can reverse obesity while animals feed on a high-fat diet. These studies should aid the development of improved tests and treatments for obesity and type 2 diabetes.

OTOPROTECTION BY ADENOSINE RECEPTORS
– $146,752 Dr Srdjan Vlajkovic, Prof Peter Thorne, Dr Detlev Boison, Prof Gary Housley
Dept of Physiology, The University of Auckland

Hearing loss affects 10-13% of New Zealanders and this prevalence will increase with the aging population. Exposure to noise and drugs toxic to the inner ear are major contributing factors to this disability. Prosthetic rehabilitation via hearing aids and cochlear implants is the only current treatment for hearing loss. Hence, it is essential to develop therapies that can ameliorate or repair injury to the delicate structures of the inner ear. We have shown that hearing loss in experimental animals exposed to traumatic noise can be substantially restored by administration of drugs acting on adenosine receptors. Here we propose a set of studies that will utilize transgenic mice that lack genes for the two main types of adenosine receptors found in the inner ear to assess their responses to aging, noise stress and drug toxicity. This is critical translational research for therapeutic management of noise, age and drug-induced hearing loss.

Picking the ideal treatment for people with schizophrenia – new project funded in the CBR

Patients with schizophrenia could soon be prescribed tailored drugs for their biology, as a new project gets underway in the Centre for Brain Research. Funding from the Auckland Medical Research Foundation has enabled promising Research Fellow Dr Valerie Anderson to undertake the research.

Standard medications are not affective in approximately a third of people with schizophrenia, and these patients are considered ‘treatment-resistant’. Alternative medication and combinations of antipsychotics must be used, but these medications have a greater risk of inducing serious side effects and therefore are avoided where possible. Consequently, people with treatment-resistant schizophrenia often experience many years of unsuccessful therapy with standard medications before alternatives are prescribed, during which time their symptoms severely affect daily living and have a significant impact on long-term outcomes.

 The Psychopharmacology team will now investigate whether they can identify measurable biological characteristics (biomarkers) that could be used to predict whether people with schizophrenia will be treatment-resistant. Brain magnetic resonance imaging, electroencephalography, and neuropsychological data will be collected and analysed to investigate the structure and function of the brain in people with schizophrenia who are treatment-resistant, and the findings compared to people with schizophrenia who respond well to standard medications and normal subjects.

 Identification of reliable biomarkers to predict treatment-resistant schizophrenia would enable alternative medications to be prescribed earlier in the disease course. This will ultimately minimise the time that these patients experience debilitating symptoms, leading to improved outcomes for them, and reducing the burden on their families and health care providers.

 The Auckland Medical Research Foundation has also funded two new PhD scholarships at the Centre for Brain Research. Foundation Executive Director Kim McWilliams says: “Many of these researchers already have and will go on to become leaders and internationally recognised in their particular discipline or field of medicine.”

 Projects:

Biomarkers for treatment resistant schizophrenia ($179,267 – two years)
Dr Valerie Anderson, Psychopharmacology and Neurodynamics

 
 
Preterm stem cell therapy (Doctoral Scholarship $122,000 – three years)
Miss Lotte van den Heuij, Fetal Physiology

Visual brain plasticity in adult humans (Doctoral Scholarship $122,000 – three years)
Mr Victor Borges, Visual Neuroscience Group

Grant funding success for CBR researchers

Scientists at the Centre for Brain Research have been awarded almost $500,000 for four new research projects. The funding comes from the Auckland Medical Research Foundation and the Neurological Foundation of New Zealand.

The studies will examine the underlying biology of brain disorders including autism and neurodegenerative disease. Potential new treatments being developed include stem cell research on induced neural precursor cells, and a clinical trials system called EpiNet.

 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. Funded by Auckland Medical Research Foundation.

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.

THE SYNAPTIC BASIS OF AUTISM ($136,351 – 1 YEAR)
Co-funded by Auckland Medical Research Foundation and the Neurological Foundation
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. Funded by Auckland Medical Research Foundation.

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.

VALIDATION OF THE EpiNet PLATFORM AND THE EpiNet STUDY GROUP

Dr Peter Bergin, Auckland City Hospital, Auckland ($85,464)

Funded by the Neurological Foundation.

In the July 2009 grant round, the Neurological Foundation approved funding for Dr Peter Bergin’s international collaborative pilot study which set up an internet-based platform to recruit patients for epilepsy drug trials. The platform, called EpiNet, is now functioning and is able to be accessed by adult and paediatric neurologists from anywhere in the world. In this second study phase, the EpiNet study group, led by Dr Bergin and involving an international collaboration of epileptologists, will undertake a study to validate both the EpiNet study group and the EpiNet platform before undertaking clinical trials. The group will circulate 50 fictitious case histories to doctors who have expressed interest in participating in the EpiNet project, and ask them to enter details into the EpiNet database, using standard and internationally approved epilepsy classification systems. Investigators’ results will be compared. As well as confirming that investigators ‘speak the same language’ globally, the study will also determine how much variability there is when classifying individual cases using the classification schemes. At the same time, the group will undertake steps to confirm that the database and systems procedures are robust.