December 2016 research grant round recipients announced

PRESS RELEASE

For immediate release: Wednesday 14 December 2016

NEUROLOGICAL FOUNDATION ANNOUNCES DECEMBER 2016 GRANT ROUND RECIPIENTS

Nearly $1.4 million committed to neurological research across New Zealand

The Neurological Foundation is pleased to announce that funding of $1,382,529 for neurological research projects, two postgraduate scholarships, three postdoctoral fellowships, and two summer studentships has been approved in its December 2016 grant round. This brings the total research funding allocated by the Foundation in 2016 to $2,723,131. The Neurological Foundation is the primary non-government funder of neurological research in New Zealand, and also sponsors the Neurological Foundation Douglas Human Brain Bank and the Neurological Foundation Chair of Clinical Neurology research programme.

Neurological Foundation Executive Director Max Ritchie says “This grant round’s recipients demonstrate the highly innovative thinking that enables New Zealand to remain at the leading edge of research into the understanding, prevention and treatment of neurological disorders. Furthermore, this innovation provides real hope for the one in five New Zealanders across all age groups who will be diagnosed with a brain disorder in their lifetime.”

The December grants allocated include the funding of the following projects:

Learning and memory:

· The role of the brain’s synaptic networks in controlling plasticity and memory

· The role of a molecular sugar in brain development

Sleep: Investigating the role of a hormone in sleep dysregulation

Brain cancer:

· How do melanoma cancer cells migrate into the brain and survive by avoiding our defensive immune system?

· Investigating a target for treatment of aggressive brain tumours

Parkinson’s disease:

· Investigating the potential improvement of the effectiveness of a Parkinson’s disease drug

· Investigating the individualised risk score for future dementia in Parkinson’s disease patients by measuring the thickness of the brain’s cortical mantle

Neurodevelopmental disorders:

· Can increased maternal dietary zinc prevent the development of autism-associated behaviours?

· A pilot study to test a training intervention paradigm for cognitive improvements in children with neurodevelopmental disorders

Stroke:

· Recovery of movement and sensation after stroke – the 70% recovery rule

· Investigating a specific pathway in the brain involved in movement recovery after stroke

Multiple sclerosis: Investigating new drug compounds for the treatment of multiple sclerosis in two pre-clinical models

All grant details follow.

NEUROLOGICAL FOUNDATION RESEARCH APPROVED DECEMBER 2016

Grants totalling $1,382,529 were approved by the Neurological Foundation Council on 2 December 2016.

NEUROLOGICAL FOUNDATION PHILIP WRIGHTSON POSTDOCTORAL FELLOWSHIPS

For researchers who have completed a PhD and wish to develop their research careers. This work can be undertaken at either New Zealand or overseas universities or hospitals.

Dr Chantelle Fourie

Department of Physiology

University of Auckland

$169,975

Interneuron networks underlying hippocampal plasticity and spatial learning and memory retrieval

The role of the brain’s synaptic networks in controlling plasticity and memory

Understanding how the brain learns and stores memories is one of the major challenges in science. Neuronal activity in the brain’s memory centre, the hippocampus, is shaped by both excitatory and inhibitory synaptic input. A synapse is a space between two neurons that serves as a junction through which nervous impulses pass so cellular communication can occur. Synaptic plasticity - the ability of synapses to strengthen/weaken their synaptic input - is thought to underlie learning and memory. Dr Fourie’s research will uncover the role of hippocampal inhibitory synaptic networks in controlling synaptic plasticity and memory. Together these experiments will provide new insights into the brain networks underlying memory and will uncover novel targets for intervention to improve learning and memory, especially in neurological disease.

Dr Fourie will undertake her Neurological Foundation Philip Wrightson Postdoctoral Fellowship at Nanyang Technological University in Singapore under the supervision of Professor George Augustine.

Using optogenetics* to investigate inhibitory networks is one of the areas of expertise of Professor Augustine, who is well-known for his studies of synaptic mechanisms in the brain. This fellowship will enable Dr Fourie to expand her expertise in inhibitory networks and investigate their role in long-term plasticity and learning behaviour, by mastering and applying the latest in vitro and in vivo optogenetic techniques.

Dr Fourie’s long-term career goal is to return to New Zealand and establish her own research group to better understand the brain networks underlying learning and memory and how they can ultimately be manipulated to improve learning and memory in neurological diseases such as Alzheimer’s disease and Autism Spectrum Disorders.

*Optogenetics is a cutting-edge technology that combines molecular biology with light stimulation to allow researchers to have precise control over the behaviour of a cell or populations of cells.

NEUROLOGICAL FOUNDATION PHILIP WRIGHTSON POSTDOCTORAL FELLOWSHIPS continued

Susan Tyree

Department of Psychiatry and Behavioral Science

Stanford University

USA

$159,779

Investigation of neural circuits mediating negative outcomes of sleep dysregulation
Investigating the role of a hormone in sleep dysregulation

Sleeping, eating, and stress are all essential for humans to survive. These functions rely on each other, but exactly how they interact is poorly understood. Sleep deprivation is associated with disrupted eating behaviours, increased stress, and increased body mass index. The hormone hypocretin has emerged as a potential key to the interlinked function of these systems. Advanced techniques now allow researchers to view neuronal circuits directly while also controlling their activity. Miss Tyree will study hypocretin neurons and their targets involved with sleep, stress, and eating behaviours in a mouse model, to confirm or deny a role for hypocretin in mediating negative consequences of sleep dysregulation.

Miss Tyree will undertake her Neurological Foundation Philip Wrightson Postdoctoral Fellowship in the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine in the United States. Her supervisor, Professor Luis de Lecea, is a global leader in the field of sleep research and his laboratory has pioneered several important discoveries in this field.

Following the completion of her Masters degree at the University of Otago, Miss Tyree was awarded a postgraduate bursary at the German Institute of Human Nutrition where she has studied for the past three years. Miss Tyree’s Stanford research will deepen and broaden her technical skill base and add cutting-edge techniques to her skill repertoire. After the completion of her Neurological Foundation Philip Wrightson Postdoctoral Fellowship, she hopes to return to New Zealand to build her own research lab where she can use her newly developed skills and international connections to further her work.

Dr Rashi Karunasinghe

Department of Physiology

University of Auckland

$180,629

Filling in the gaps in the brain: the developmental roles of extracellular hyaluronan in neuronal signalling and plasticity

The role of a molecular sugar in brain development

The brain is a complex organ with a remarkable ability to remodel its circuitry. This unique feature, termed ‘plasticity,’ dynamically modifies the signalling between brain cells. For example, brain plasticity is important during learning and encoding memories. On the other hand, a stabilisation of circuits is responsible for the consolidation of existing memories. The mechanisms involved in regulating brain plasticity (versus stability) are not well understood. Dr Karunasinghe’s preliminary research findings indicate intriguing roles for an extracellular matrix sugar called hyaluronan. This project will follow how neurons regulate hyaluronan levels in order to modify their molecular, structural, and electrophysiological properties during brain development.

Neurological Foundation Gillespie Postgraduate Scholarship

Akshata Anchan

Department of Pharmacology and Clinical Pharmacology

University of Auckland

Supervisor: Dr Scott Graham

$104,499

Migration of metastatic melanoma cells across the blood brain barrier and manipulation of brain microenvironment via checkpoint blockade

How do melanoma cancer cells migrate into the brain and survive by avoiding our defensive

immune system?

The brain is a preferential metastatic site for several types of cancer including melanoma. Melanoma is one of the most aggressive forms of cancer, and New Zealand has one of the highest incidence rates in the world. While melanoma is more common in people over 50 years of age, it is the most commonly diagnosed cancer in 15 - 29 year olds. People with metastasised melanoma (where the cancer has spread from the original tumour site) have limited survival, especially when the destructive melanoma cells metastasise to the brain. Because the brain is an extensively defended organ, it is of great interest to researchers how cancer cells manage to invade the protective blood-brain barrier. The specificities of how this happens are not well studied in human cells. Ms Anchan’s research aims to investigate human melanoma cells to discover the key components that allow them to 1: migrate into the brain and 2: survive within the brain by avoiding our defensive immune system. Ms Anchan hopes to follow this study by researching ways to block these processes.

Neurological Foundation W & B Miller Postgraduate Scholarship

Nicole Edwards

Department of Pharmacology and Clinical Pharmacology

University of Auckland

Supervisor: Associate Professor Bronwen Connor

$104,499

Modelling the neurodevelopmental disorder Fragile X Syndrome by Direct Reprogramming
Developing an authentic research model of Fragile X Syndrome using an innovative New Zealand-developed technology

Fragile X Syndrome (FXS) is the most common genetic cause of intellectual disability and autism, and has been linked to impaired neuronal development and function. To overcome the lack of access to live developing human neurons, Ms Edwards’ supervisor, Associate Professor Bronwen Connor, has developed a strategy to generate immature brain cells directly from adult human skin through a technique called direct reprogramming. Ms Edwards’ postgraduate work will use this technique to generate immature brain cells directly from FXS patients to investigate changes in the expression of genes and proteins important for neuronal development and function. This project will establish a human model of FXS and progress the understanding of this disorder.

Ms Edwards’ study will build on the large body of cell-reprogramming research work that Associate Professor Bronwen Connor’s laboratory is internationally well-regarded for.

PROJECT GRANTS

Dr Scott Graham

Department of Pharmacology and Clinical Pharmacology

University of Auckland

$12,000

Which inhibitory immune checkpoint control proteins are expressed in human brain tumours?

Investigating a target for treatment of aggressive brain tumours

There is a clear and present need for better treatments for brain cancers. Immune “checkpoints” critically govern many aspects of our immune response to tumour cells, and are key regulators of T-cell activation, proliferation and function. T-cells are a subtype of white blood cells which play a key role in the immune system and in fighting cancer. Immunotherapies targeting the immune-checkpoint control axis are proving to be the greatest breakthrough for advanced melanoma and several other types of aggressive cancer. These molecules offer incredible potential in brain cancer to suppress the tumour cells or switch on the correct T cell responses. First however, we must understand the repertoire of their expression in brain tumours and identify those that represent the best targets; this is the aim of Dr Graham’s research project.

Dr Karl Iremonger

Department of Physiology

University of Otago

$11,615

Imaging the activity of stress neurons in vivo

Using cutting-edge technology to image the activity of stress neurons in a mouse model

Excessive activation of brain stress circuitry results in high levels of stress hormones in our body, which can damage our body and brain. Our understanding of this circuitry has been limited as no study has been able to observe the activity of stress neurons in the intact brain. Using cutting-edge genetic and optical techniques, Dr Iremonger’s project aims to record the activity of stress neurons in freely behaving mice. Understanding how these neurons are regulated could lead to future tools that can be used to normalise stress neuron excitability in neurological conditions associated with high stress.

Dr Iremonger’s study is generously supported by Mr Jeremy Collins.

Professor Janusz Lipski

Department of Physiology

University of Auckland

Associate Investigator:

Professor Brian Hyland

Department of Physiology

University of Otago

$168,760

Preclinical efficacy of Uptake-2 blockers in augmenting dopamine production from levodopa: implications for treatment of Parkinson’s disease

Investigating the potential improvement of the effectiveness of a Parkinson’s disease drug by inhibiting a mechanism in a rat brain model

Parkinson’s disease is a brain disorder which affects 1-2% of people older than 65 in New Zealand and worldwide, leading to numerous symptoms including tremor in the hands, slowness of movement, stiff muscles and slurred speech. The most widely prescribed treatment relies on levodopa, a drug which replenishes a chemical dopamine lost in the course of the disease. However, after prolonged use, the effects of the drug become progressively shorter, prompting doctors to increase the dosage. Unfortunately, this frequently leads to serious, undesirable side effects. Professor Lipski’s study aims to improve the effectiveness of levodopa treatment by inhibiting a recently discovered mechanism which inactivates dopamine. This will be studied in a rat model. If successful, this strategy will inform clinical administration of levodopa doses with the aim of using lower doses for a longer period of time, hopefully minimising the occurrence of side-effects while maintaining therapeutic effectiveness of the drug. Professor Lipski’s ultimate goal is to reduce the suffering and improve quality of life of those affected by Parkinson’s disease.

Dr Tracy Melzer

Department of Medicine

University of Otago, Christchurch

2014 Neurological Foundation Philip Wrightson Postdoctoral Fellow

$162,422

Individual risk of dementia: enhanced precision with cortical thickness

Investigating the individualised risk score for future dementia in Parkinson’s disease patients by measuring the thickness of the brain’s cortical mantle

Parkinson’s disease (PD) affects approximately 10,000 New Zealanders, and the incidence is increasing rapidly with our ageing population. Progression to dementia is a primary health care issue for PD patients and carers, but doctors cannot yet predict this progression. Using clinical and brain imaging data, Dr Melzer will create a method of generating an individualised risk score for dementia over time, including a measurement of the thickness of the cortical mantle in the brain. Such a unique advance in precision and personalised medicine would enable informed discussion between doctor, patient and carer about prognosis and life-choices. It would also provide a mechanism for recruiting the appropriate “at risk” people with Parkinson’s disease into new trials of therapies aiming to prevent dementia.

Associate Professor Johanna Montgomery

Department of Physiology

University of Auckland

$11,920

Can increased maternal dietary zinc prevent the development of autism-associated behaviours?

Autism Spectrum Disorders (ASD) are characterised by impaired communication and social behaviours. ASD-related genetic changes frequently occur in proteins at synapses, impairing brain cell communication. A synapse is a space between two neurons that serves as a junction through which nervous impulses pass so cellular communication can occur. In previous studies, Associate Professor Montgomery’s data show that zinc increases brain cell communication, so zinc could be a target treatment strategy for ASD. This study aims to determine whether increased dietary zinc during pregnancy and lactation can prevent the development of ASD behaviours in a mouse model of ASD, and whether this is associated with changes in synapses. Together, the data will characterise, from synapse to behaviour, the potential of dietary zinc in ASD during brain development.

Dr Justin Dean

Department of Physiology

University of Auckland

$11,788

Promoting myelination for functional recovery after subcortical white matter stroke – development of an endothelin-1 animal model

Investigating a specific pathway in the brain involved in movement recovery after stroke using a rat model

Stroke is a leading cause of adult disability, affecting 8,000 New Zealanders each year. Recovery of movement is crucial to regaining independence after stroke. Although no two strokes are exactly alike, New Zealand researchers Professor Winston Byblow and Associate Professor Cathy Stinear, co-investigators on this project, have demonstrated that motor recovery occurs to almost exactly 70% of the maximum possible for the majority of stroke patients, provided a key pathway in the brain is intact. This project will establish an animal model to investigate the mechanisms of recovery along this pathway in the brain. This will allow the research team to identify novel therapeutic targets which may raise the recovery ceiling above 70%.

Dr David Moreau

School of Psychology

University of Auckland

$11,640

Enhancing cognition: brain networks underlying effective training interventions

A pilot study to test a training intervention paradigm for cognitive improvements in children with neurodevelopmental disorders

One in five children faces difficulty learning because of an underlying disorder such as ADHD, dyslexia, dyscalculia and dyspraxia. No matter how hard they try, these children have to overcome major hurdles to succeed academically. Claims of cognitive enhancement using behavioural training have recently sparked interest, given their potential to elicit wide-ranging improvements along with very few side effects. Dr Moreau and colleagues have developed a training intervention that has the potential to alleviate some of the negative effects of neurodevelopmental disorders. This initiative places the culmination of decades of research at the service of remediation. While typical interventions targeting learning disorders come at it from a single angle, Dr Moreau and his team are tackling this problem on multiple fronts. Their unique approach combines a blend of exercise with a software regimen tailored to each individual. Ultimately, this work could also impact remediation of the injured and ageing brain, paving the way for novel therapeutic interventions.

Dr Bronwyn Kivell

School of Biological Sciences

Victoria University of Wellington

$145,947

Investigating the therapeutic potential of novel kappa opioids for the treatment of multiple sclerosis

Investigating new drug compounds for the treatment of multiple sclerosis in two pre-clinical models

Multiple sclerosis (MS) is a debilitating neurological disease with no cure. In MS the body’s own immune system attacks and destroys the protective myelin coating surrounding nerve cells causing a variety of symptoms such as fatigue and muscle weakness, and ultimately leads to paralysis. Recently, a new therapeutic target called the kappa opioid receptor was shown to activate the cells that repair damaged myelin. A drug that activated this protein was shown to reverse paralysis in pre-clinical models of MS. Dr Kivell’s study has access to a library of novel kappa opioid compounds with increased potency, improved pharmacokinetic properties and significantly fewer side effects compared with the drug used in the previous study. Dr Kivell and co-investigators including Associate Professor Anne La Flamme, will test these new compounds in two models of MS and evaluate the mechanisms underlying the therapeutic effects of these novel drugs. If successful, this research has potential to significantly improve the quality of life of MS patients globally.

Associate Professor Cathy Stinear

Department of Medicine

University of Auckland

$115,056

Spontaneous recovery of sensorimotor impairment after stroke

Recovery of movement and sensation after stroke – the 70% rule

Stroke affects more than 8,000 New Zealanders each year and is a leading cause of adult disability. Clinical neuroscientist Associate Professor Cathy Stinear and colleagues Professors Alan Barber and Winston Byblow recently made the remarkable discovery that patients routinely recover 70% of the movement they have lost after stroke. This 70% rule applies to all patients, provided a key pathway in the brain is preserved, regardless of their age or how much therapy they complete. This suggests that a fundamental biological process is at work, which is yet to be identified. In this study, Associate Professor Stinear and co-investigators Professors Barber and Byblow will use neurophysiology and neuroimaging techniques to explore the processes underlying the 70% rule. The team will also be the first to study the recovery of sensory function, to see whether it also follows the 70% rule. Understanding the processes responsible for spontaneous recovery will identify new therapeutic targets to improve recovery after stroke.

SUMMER STUDENTSHIPS

The C and N Anderson Summer Studentship

Eli Shaul

Department of Anatomy with Medical Imaging

University of Auckland

Supervisor: Associate Professor Maurice Curtis

$6,000

Optimising lipid antibodies to assess changes in Alzheimer’s disease hippocampus
Identifying the involvement of lipids in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common form of dementia and accounts for approximately 60% of all dementia cases in New Zealand. It is estimated that 28,000 New Zealanders are living with AD. The key to better treatments is a greater understanding of the pathogenesis and brain changes that occur in this disease. Though amyloid plaques and tau tangles are the pathological hallmarks of Alzheimer’s disease, there is also evidence of the involvement of lipids in AD pathology. Lipids are naturally occurring organic compounds and the human brain is the most lipid-rich organ in the human body. In this project Mr Shaul will optimise a new method of detecting lipid changes in the brain that will allow correlation between other technological techniques that also detect lipid changes. The overall aim is to understand which lipids are affected in AD as a first step to manipulating them to better treat Alzheimer’s disease.

Niamh Cameron

Department of Anatomy

University of Otago

Supervisor: Associate Professor Louise Parr-Brownlie

$6,000

Establishing a rat model of complex regional pain syndrome (CRPS)

Pain is an uncomfortable sensation that we all experience from time-to-time, but for one in five of us it becomes chronic and may last for many months or even years. One chronic pain condition called complex regional pain syndrome (CRPS), a neuropathic pain disorder, often begins with a fracture which develops into sensitivity to touch, heat and cold. Few effective medical treatments are available. Clinicians and researchers have a poor understanding of how and why CRPS occurs. As a first step towards finding better treatments, Ms Cameron will create a model of CRPS to enable researchers to explore changes in the brain associated with chronic pain.

ENDS

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