MND research grants 2020

PROJECTS COMMENCING IN 2020

BETTY LAIDLAW MND RESEARCH PRIZE 2020
Dr Shyuan Ngo  University of Queensland, QLD	Betty Laidlaw MND Research Prize awarded to an outstanding mid-career researcher	From the nucleus to the powerhouse: investigating how TDP-43- mitochondrial interactions wreak havoc in MND

POSTDOCTORAL FELLOWSHIPS (2020 – 2022)
Dr Luke McAlary University of Wollongong, NSW	Bill Gole MND Postdoctoral Fellowship 2020 – 2022	Targeting Prion-Like Strains of TDP-43
Dr Mehdi van den Bos Westmead Hospital, NSW	Beryl Bayley MND Postdoctoral Fellowship 2020 – 2022	Deep learning as a tool to advance the diagnosis and pathophysiological understanding of ALS

INNOVATOR GRANTS
Associate Professor Bradley Turner Florey Institute of Neuroscience and Mental Health, VIC	Charcot Grant awarded to the highest ranking innovator grant application	Development of a novel splice-switching molecular therapy for MND
Professor Julie Atkin  Macquarie University, NSW	Peter Stearne Familial MND Research Grant	Novel mechanisms of neurodegeneration induced by dysfunctional actin dynamics in MND
Dr Samantha Barton  Florey Institute of Neuroscience and Mental Health, VIC	Jenny Simko MND Research Grant	Could abnormal myelin composition be exacerbating neuronal dysfunction in MND?
Professor David Berlowitz  Austin Health/University of Melbourne, VIC	Mavis Gallienne and Graham Lang MND Victoria Research Grant	NIV@Home
Dr Richard Gordon University of Queensland, QLD	Col Bambrick MND Research Grant	Targeting inflammasome-driven neuropathology and motor neuron death in MND using a clinically approved cancer drug
Dr Albert Lee Macquarie University, NSW	MNDRIA Innovator Grant	Clearance of TDP-43 by PROteolysis Targeting Chimera (PROTAC) dual targeting to treat amyotrophic lateral sclerosis (ALS)
Dr John Lee University of Queensland, QLD	MNDRIA Innovator Grant	Investigating the therapeutic inhibition of CXCR2 as a disease modifying treatment for motor neurone disease
Dr Susan Mathers Calvary Health Care Bethlehem/Monash University, VIC	Superball XI MND Research Grant	Identifying and responding to the health literacy needs of people living with MND/ALS – a coordinated national approach
Professor Pamela McCombe  University of Queensland, QLD	MNDRIA Innovator Grant	Possible gut derived toxins in ALS: prevalence and effects on outcome
Dr Fiona McKay University of Sydney, NSW	MNDRIA Innovator Grant	Natural Killer cells in amyotrophic lateral sclerosis
Dr Marco Morsch  Macquarie University, NSW	MonSTaR MND Research Grant	The unexplored posttranslational modification (SUMOylation) of TDP43 affects aggregate formation and localisation
Associate Professor Lezanne Ooi University of Wollongong, NSW	Benalla Act to d'feet MND Research Grant	Targeting cortical hyperexcitability and neurodegeneration in amyotrophic lateral sclerosis
Dr Mary-Louise Rogers  Flinders University, SA	MNDRIA Innovator Grant	Urinary Neopterin as a candidate biomarker that can be used to test disease progress in clinical trials for Motor Neurone Disease
Dr Frederik Steyn  University of Queensland, QLD	Fat Rabbit MND Research Grant	Tipping the Scales on MND: Preclinical testing of a compound with multiple actions to slow disease progression in MND
Dr Sicong Tu University of Sydney, NSW	MonSTaR MND Research Grant	Utilising multi-modal connectivity and artificial intelligence to track disease progression in ALS/MND
Dr Kara Vine University of Wollongong, NSW	Run MND NSW Research Grant	Non-invasive drug delivery across the blood brain barrier: Improving the bioavailability of drugs for MND
Dr Adam Walker University of Queensland, QLD	MNDRIA Innovator Grant	New mouse models of TDP-43 pathology
Associate Professor Anthony White QIMR Berghofer Medical Research Institute, QLD	NTI MND Research Grant	Boosting microglia phagocytosis as a therapeutic approach to treat MND
Dr Kelly Williams Macquarie University, NSW	Robert Turnbull MND Research Grant	Comprehensive transcriptome analysis of neuroanatomical regions with variable pTDP-43 pathology in sporadic ALS patients
Associate Professor Trent Woodruff University of Queensland, QLD	MNDRIA Innovator Grant	Transcriptomic and Functional Evaluation of Immune-Activated Monocytes in MND

 

MULTI-YEAR GRANTS FROM PREVIOUS YEARS CONTINUING IN 2020

 

POSTDOCTORAL FELLOWSHIPS (2019 – 2021)
Dr Rosemary Clark University of Tasmania, TAS	Bill Gole MND Postdoctoral Fellowship 2019 – 2021	Clinical heterogeneity in ALS: insights from interneurons?
Dr James Hilton University of Melbourne, VIC	Beryl Bayley MND Postdoctoral Fellowship 2019 – 2021	Ferroxidase dysfunction drives glial ferroptotic stress and motor neurone death via neurotoxic A1 astrocyte conversion

 

POSTDOCTORAL FELLOWSHIPS (2018 – 2020)
Dr Nirma Perera Florey Institute of Neuroscience and Mental Health, VIC	Bill Gole MND Postdoctoral Fellowship 2018 – 2020	Targeting autophagy protein homeostasis pathway to improve motor neurone health in MND
Dr William Huynh Brain and Mind Centre, University of Sydney, NSW	Beryl Bayley MND Postdoctoral Fellowship 2018 – 2020	A multimodal approach combining novel electrophysiological and neuroimaging techniques to explore the pathophysiological mechanisms and patterns of disease spread in MND

 

MNDRIA PhD SCHOLARSHIP TOP-UP GRANT
Megan Dubowsky Flinders University, SA	MNDRIA PhD Scholarship Top-Up Grant 2019 - 2021	Endogenous retroviruses as a cause of motor neurone disease
Marcus Dyer University of Tasmania, TAS	MNDRIA PhD Scholarship Top-Up Grant 2019 - 2021	Neuronal excitability in ALS – a focus on TDP-43 mislocalisation
Camille Paynter University of Melbourne, VIC	MNDRIA PhD Scholarship Top-Up Grant 2018 - 2020	A longitudinal study of involvement in health care decision-making in motor neurone disease: Patient and caregiver perceptions, impact of communication and swallowing difficulties, and quality of life
Britt Berning Queensland Brain Institute, QLD	MNDRIA PhD Scholarship Top-Up Grant 2018 - 2020	Sub-cellular dysfunctions associated with pathological TDP-43 in MND: disease mechanisms and therapeutic relevance

PROJECTS COMMENCING 2020

Betty Laidlaw MND Research Prize

Dr Shyuan Ngo
University of Queensland, QLD

From the nucleus to the powerhouse: investigating how TDP-43- mitochondrial interactions wreak havoc in MND
In MND, the TDP-43 protein forms clumps inside neurons. While we know that these clumps of TDP-43 are toxic to the cell, we don’t know how this leads to neuronal death. We will use neurons made from human skin cells to study whether interactions between TDP-43 and mitochondria (the powerhouse of the cell) causes a breakdown in the mitochondrial network, and an inability of mitochondria to function properly, ultimately leading to the death of neurons. This will allow us to identify a key cause for the death of neurons in MND; a critical step towards developing treatments.

Bill Gole MND Postdoctoral Fellowship (2020 – 2022)

Dr Luke McAlary
University of Wollongong, NSW

Targeting Prion-Like Strains of TDP-43
Toxic proteins in MND are capable of spreading from cell to cell in the spinal cord and brain by recruiting normal healthy protein. This spread is controlled by the shape of the toxic protein, some shapes spread more readily than others. Advanced imaging technologies have been produced where we can see the shape of individual proteins. We plan to use these imaging technologies to define the shape(s) of toxic MND proteins and apply a broad set of drug discovery methods to identify the best drugs to target them.
 

Beryl Bayley MND Postdoctoral Fellowship (2020 – 2022)

Dr Mehdi van den Bos
Westmead Hospital, NSW

Deep learning as a tool to advance the diagnosis and pathophysiological understanding of ALS
ALS can be a difficult disease to diagnose and is proving even more challenging to cure. Increasingly we are realising that early intervention is needed and there are many signs brain overactivity is an early driving cause of the disease. This fellowship proposes to use advanced neurophysiological methods (probing brain function with magnetic brain stimulation and brain wave recordings) together with artificial intelligence (the technique of deep learning) to make possible early diagnosis, improve our understanding of the drivers of the disease in patients and find a reliable biological marker to accelerate drug trials that will deliver a cure.
 

Charcot Grant

Associate Professor Bradley Turner
Florey Institute of Neuroscience and Mental Health, VIC

Development of a novel splice-switching molecular therapy for MND ​
Mutations in the SOD1 gene are a common cause of MND. We have developed a novel therapy using powerful genetic designer drugs which target and 'turn off' the offending SOD1 gene. In this project, we will comprehensively test our therapeutic approach in motor neurons grown from MND patients and in MND mice. We predict our therapy will significantly slow down disease and protect motor neurons in MND mice due to suppression of the SOD1 gene. This will provide crucial support for continued development of our genetic therapy approach for MND.
 

Peter Stearne Familial MND Research Grant

Professor Julie Atkin 
Macquarie University, NSW

Novel mechanisms of neurodegeneration induced by dysfunctional actin dynamics in MND
Actin is the most abundant protein in humans. It has many important functions, including forming the synapses that enable nerve cells to talk to each other to co-ordinate movement and brain activites. To perform these functions, actin continuously assembles and disassembles to form long filaments. Abnormalities in actin are known to be present in Alzheimer’s and Parkinson’s disease but it is unknown if they exist in MND. However we have obtained exciting new evidence that actin is also abnormal in MND. This project will examine how this occurs and whether already available drugs that regulate actin are protective in MND.
 

Jenny Simko MND Research Grant

Dr Samantha Barton 
Florey Institute of Neuroscience and Mental Health, VIC

Could abnormal myelin composition be exacerbating neuronal dysfunction in MND? 
Oligodendrocytes (a type of glial cell that forms myelin) have two key roles essential for motor neuron function: to myelinate (coat) neurons and to provide sources of energy to neurons. In MND, both functions are impaired but the contribution to neuronal dysfunction remains unknown. We will comprehensively assess oligodendrocyte function in post-mortem tissue and then interrogate mechanisms of dysfunction using a highly innovative stem cell model whereby we take MND patient stem cells and turn them into mini-brain structures in the lab. Identifying the cause of altered myelination and energy production will address a gap in current knowledge and highlight the relevance of oligodendrocytes when searching for effective therapies.

Mavis Gallienne and Graham Lang MND Victoria Research Grant

Professor David Berlowitz 
Austin Health/University of Melbourne, VIC

NIV@Home
Approximately 80 people with MND start non-invasive ventilation (NIV) annually in Victoria. NIV is currently established with a same-day hospital admission and then another overnight stay within two months. These admissions are burdensome and time consuming for patients, their families and carers. An ever increasing demand for inpatient beds can also delay access to NIV further increasing burden and anxiety. Once on NIV, trouble-shooting involves hospital attendance or a home visit from Outreach nursing. NIV@Home will pilot whether substituting inpatient admissions and sleep studies with home implementation and telehealth results in equivalent NIV usage but a better patient experience.

Col Bambrick MND Research Grant

Dr Richard Gordon
University of Queensland, QLD

Targeting inflammasome-driven neuropathology and motor neuron death in MND using a clinically approved cancer drug
Chronic activation of the immune system and persistent inflammation in Motor Neuron Disease (MND) are considered to be key drivers of motor neuron loss. Breaking this cycle of inflammation and motor neuron death is currently considered one of the most promising treatment approaches for MND. In this study, we will test a promising FDA-approved drug which we believe can block both inflammation and death of motor neurons in MND. Most importantly, since this drug is already approved for human use, it can directly progress into clinical trials for MND if the outcomes of our research are positive.
 

MNDRIA Innovator Grant

Dr Albert Lee
Macquarie University, NSW

Clearance of TDP-43 by PROteolysis Targeting Chimera (PROTAC) dual targeting to treat amyotrophic lateral sclerosis (ALS) 
The pathological feature of MND is the presence of protein inclusions inside motor neurons – comprising mostly of the protein TDP-43. TDP-43 inclusions are a major contributor to disease, and therefore we are investigate ways to prevent formation and clearance of these TDP-43 inclusions. We have identified a protein that binds TDP-43 in motor neurons, and we will use this information to construct a therapeutic intervention that combines this with a new technology called PROteolysis TArgeting Chimera (PROTAC). We will perform pre-clinical evaluation of our PROTAC to specifically target and clear TDP-43 from neurons, to restore normal cellular function and health.

MNDRIA Innovator Grant

Dr John Lee
University of Queensland, QLD

Investigating the therapeutic inhibition of CXCR2 as a disease modifying treatment for motor neurone disease
Increased activity of our immune system can contribute to MND. One component that is gaining momentum as key driver of neuron death is CXCR2. CXCR2 is known to recruit our immune cells to site of injury. We believe that unwanted activity of CXCR2 is contributing to MND progression. This study will use a drug that will block CXCR2 in mouse models of MND, and in MND patient samples, to understand if this drug can dampen immune response and protect motor neurons. This will help determine whether targeting CXCR2 may be a viable therapeutic option to benefit people with MND.
 

Superball XI MND Research Grant

Dr Susan Mathers
Calvary Health Care Bethlehem/Monash University, VIC

Identifying and responding to the health literacy needs of people living with MND/ALS – a coordinated national approach 
This project aims to understand how easy or difficult it is for people with Motor Neurone Disease (MND) to find, understand and make use of information about managing their life with the disorder. Specifically, what help do these people, together with their families or carers, need to make the decisions which are best for them? It also intends to explore how people living with MND interact with those providing information and advice on their care. Lastly the project aims to develop innovative ways of providing information and delivering health care that consumers of health services find useful and that support decision-making.
 

MNDRIA Innovator Grant

Professor Pamela McCombe 
University of Queensland, QLD

Possible gut derived toxins in ALS: prevalence and effects on outcome
Some of the risk of ALS is genetic and the remainder is non-genetic (environmental). In this study we will look for circulating neurotoxins in the blood of patients with ALS. This is based on preliminary studies that have already shown that some patients have elevated levels of formaldehyde and D-serine. This is significant because the source of these toxic molecules could be the gut microbiota. Some microbes, such as the Archaea could produce these toxins. This could provide a possible explanation for how gut dysbiosis could contribute to disease and provide opportunities for treatment.

MNDRIA Innovator Grant

Dr Fiona McKay
University of Sydney, NSW

Natural Killer cells in amyotrophic lateral sclerosis
The immune system is intimately involved in the disease process in MND and influences the rate of disease progression. This project examines a potent immune cell type called the “natural killer cell” in MND. Natural killer cells are increased in the blood in MND and found in the spinal cord in the mouse model of disease but their role in MND is unknown. We will characterise NK cells in MND patients and their relationship with disease and the inflammatory process, as well as the effects of an antiinflammatory therapy, dimethyl fumarate, on NK cells in MND.
 

MonSTaR MND Research Grant

Dr Marco Morsch 
Macquarie University, NSW

The unexplored posttranslational modification (SUMOylation) of TDP43 affects aggregate formation and localisation
Aggregation of the protein called TDP-43 is a hallmark feature of ALS. The movement of TDP-43 out of the nucleus appears to be detrimental for neuron survival. For TDP-43 to localise into the right compartment, it undergoes post-translational modifications (PTMs). We recently found for the first time that one of these PTM-pathways (SUMOylation) is critical for the localisation of TDP-43 aggregates, nerve growth and cell-viability. In this proposal we aim to assess the implications of SUMOylation in vivo and in patient tissue. Importantly, the SUMOylation pathway has been recently demonstrated to be a promising therapeutic target in other neurodegenerative diseases.

Benalla Act to d'feet MND Research Grant

Associate Professor Lezanne Ooi
University of Wollongong, NSW

Targeting cortical hyperexcitability and neurodegeneration in amyotrophic lateral sclerosis 
The processes that control how motor neurons communicate with one another are affected even before symptom onset in ALS. Since these changes in electrical properties are common to familial and sporadic ALS, these mechanisms are likely important in disease onset and progression. We have identified how and why these electrical properties of motor neurons change and now we will test whether preventing these changes, using pharmacological and genetic approaches, can protect motor neurons from degeneration.
 

MNDRIA Innovator Grant

Dr Mary-Louise Rogers 
Flinders University of South Australia, SA

Urinary Neopterin as a candidate biomarker that can be used to test disease progress in clinical trials for Motor Neurone Disease
We have identified a protein in urine of people with MND called p75ECD that can track progress of the disease. This was a significant break-through, with our laboratory being world leaders in urinary MND biomarkers. We will now examine an additional novel urinary biomarker called Neopterin, which is known to be influenced by immune status. We will determine if urinary neopterin levels in MND patients are different to healthy people useful for clinical trials to measure disease progress. Neopterin will also be compared to urinary p75ECD. The development of urinary biomarkers is critical to success of finding useful MND therapies.
 

Fat Rabbit MND Research Grant

Dr Frederik Steyn 
University of Queensland, QLD

Tipping the Scales on MND: Preclinical testing of a compound with multiple actions to slow disease progression in MND
MND is a complex and variable disease, and so to treat MND, this project will advance testing of a compound that will target multiple components of disease. We will test a compound with multiple proposed biological effects; including metabolic, neuroprotective and anti-inflammatory properties. By reducing the metabolic and inflammatory effects of MND, and through protecting neurons, it is thought that this compound will slow the progression of disease and extend survival in a number of mouse models of MND. These models represent a range of MND-subtypes, including familial and sporadic forms of disease. These studies are the first step towards developing a treatment that could benefit patients across the spectrum of MND.
 

MonSTaR MND Research Grant

Dr Sicong Tu
University of Sydney, NSW

Utilising multi-modal connectivity and artificial intelligence to track disease progression in ALS/MND
The absence of objective clinical markers for monitoring and predicting disease progression is a significant barrier undermining clinical care and successful clinical trial outcomes in ALS/MND. Multi-modal brain connectivity and artificial intelligence modelling are two cutting-edge techniques at the forefront of neuroscience research. This project seeks to develop these techniques in ALS/MND to advance our understanding of disease progression and develop robust and objective clinical tools for monitoring and predicting disease trajectory to improve clinical care and provide sensitive outcome measures for future therapeutic trials.
 

Run MND NSW Research Grant

Dr Kara Vine
University of Wollongong, NSW

Non-invasive drug delivery across the blood brain barrier: Improving the bioavailability of drugs for MND
A problem treating Motor Neurone Disease is the blood–brain barrier (BBB). The BBB prevents the passage of certain drugs from the blood into the brain. We have designed a drug carrier that can increase the delivery of drugs into the brains of mice with MND. We will enhance this delivery further using focused ultrasound to temporarily and safely disrupt the BBB, thereby increasing drug delivery into the brain. This project will be the first validation in rodents of an ultrasound-mediated delivery strategy for MND and will allow for the immediate scale up and further testing of our novel approach. 
 

MNDRIA Innovator Grant

Dr Adam Walker
University of Queensland, QLD

New mouse models of TDP-43 pathology 
Most people with MND develop pathology in neurons that contains the protein TDP-43. This protein undergoes many biochemical alterations, but how this relates to disease remains unclear. This project will use newly developed virus technology to produce several different pathology-associated variants of TDP-43 in mice. This will allow us to create new mouse models that will be useful for both investigating disease mechanisms as well as testing treatments for MND.
 

NTI MND Research Grant

Associate Professor Anthony White
QIMR Berghofer Medical Research Institute, QLD

Boosting microglia phagocytosis as a therapeutic approach to treat MND
Abnormal immune function in the brain has an important role in MND, but the development of new drugs to target this process has been hampered by a lack of effective model systems in which to test drugs. We have developed a new platform using human microglia (the resident immune cell of the brain) grown from blood cells of people with MND. In this project, we will use this platform to screen new and repurposed drugs for their ability to promote normal function of microglia in MND. This will greatly improve the likelihood of new drug treatments for people with MND.
 

Robert Turnbull MND Research Grant 

Dr Kelly Williams
Macquarie University, NSW

Comprehensive transcriptome analysis of neuroanatomical regions with variable pTDP-43 pathology in sporadic ALS patients
Sporadic ALS cases show a hallmark pathology in the central nervous system (CNS), however the quantity and location of this pathology can vary greatly amongst cases. We aim to investigate differences in gene expression in various regions of the CNS to understand the biological mechanisms that underly this variable pathology and why some CNS regions may be ‘protected’ from developing the pathology. We also aim to determine whether the gene expression changes are also present in patient blood samples, with the potential to be used as a disease biomarker.
 

MNDRIA Innovator Grant

Associate Professor Trent Woodruff
University of Queensland, QLD

Transcriptomic and Functional Evaluation of Immune-Activated Monocytes in MND
The immune system is now recognised to be different in MND. Alterations in both protective immune cells, as well as ‘disease-driving’ immune cells, can accelerate MND progression. Our research has identified an immune cell (called monocytes) and a key inflammatory protein (called C5a) that are elevated in patients with MND and linked to distinct disease presentations. This project will investigate both monocytes and C5a in healthy volunteers and MND blood, and identify alterations in genes and cell functions. This will provide important information that could help accelerate the progression of novel drugs targeting these factors.

  The project aims to determine the mechanisms underlying the development of this devastating neurodegenerative disorder and in particular, the site of disease onset. This project will result in highly significant advances in the understanding of MND pathophysiology, addressing an issue of great importance to human health given its rapidly progressive course. Importantly, the findings will result in fundamental outcomes in the understanding of MND pathogenesis by establishing cortical dysfunction as a primary pathogenic mechanism in MND. The findings will translate rapidly into clinical medicine by transforming the therapeutic approaches in MND, leading to novel therapeutic targets and cell based approaches.
 

Bill Gole MND Postdoctoral Fellowship (2018 – 2020)

MNDRIA PhD Scholarship Top-Up Grants (2019 – 2021)

MNDRIA PhD Scholarship Top-Up Grants (2018 – 2020)

Camille Paynter
University of Melbourne, VIC

A longitudinal study of involvement in health care decision-making in motor neurone disease: Patient and caregiver perceptions, impact of communication and swallowing difficulties, and quality of life.

Many people with MND will experience communication impairment. Difficulty with communication results in vulnerability, reduced quality of life and increased reliance on caregivers for communication support. By improving our understanding of the experiences of people with MND and their caregivers about their involvement in healthcare decision-making, we can enhance patient-centred practice.
This research will explore the facilitators and barriers for effective involvement in healthcare decision-making in MND particularly focusing on the impact of a communicating impairment. Interviews will be conducted over 12-18 months to uncover how decision-making changes over time, as disease progresses, and function and communication deteriorates.
The complexity of decision-making in MND will be captured through the longitudinal mixed methods design of this research.


Britt Berning
Queensland Brain Institute, QLD

Sub-cellular dysfunctions associated with pathological TDP-43 in MND: disease mechanisms and therapeutic relevance

Motor neurons are complex cells that require the precise and efficient movement of many different internal parts to survive. I aim to discover molecules that may be targeted for the development of new treatments for patients with MND by investigating how the movement of different parts of motor neurons is affected in disease. I will take a multi-faceted approach, combining a mouse model of MND with studies in cell culture and human brain and spinal cord samples. Manipulating key pathways related to subcellular movement may prevent neuron death and help remove the toxic aggregates that are a hallmark of MND.