ProfessorTracey Dickson

Project Total: $97,812; To map the genetic and epigenetic changes that drive brain tumour development. Funded by: Walter and Eliza Hall Institute of Medical Research ($97,812); University of Tasmania.

Project Total: $99,809; Diverse lines of evidence suggest that the -aminobutyric acid (GABA)-ergic system is altered in ALS brains, including evidence of reduced GABA, decreased binding of GABA at the main inhibitory receptor GABAA , as well as reduced expression of the main GABA producing enzyme GAD67. It has been hypothesised that this loss of GABAergic function may be responsible for ineffective inhibition and failure to prevent subsequent glutamatergic excitotoxicity leading to motor neuron loss and neurodegeneration in ALS patients. However, surprisingly, the effect of reduced GABA levels on motor function, pathology and survival has never been directly investigated in ALS in vivo, nor is it clear how reduced inhibition effects different modes and functions of inhibitory signaling in the cortex. This lack of knowledge represents a substantial barrier to the targeting of what might be a valuable therapeutic option for the treatment of ALS/MND. In the present grant, we propose to investigate the effect of reduced GABA on the disease progression and pathology in an ALS mouse model with GAD67 haploinsufficiency. To do this, we will cross the well characterised SOD1G93A mouse model with a mouse with Gad67 haploinsufficiency that is caused by replacing one allele of GAD67 with green fluorescent protein (GFP). We will test the hypothesis that 'reduced GABA will hasten disease development' directly addressing the inhibitory insufficiency theory of ALS, using a combination of motor behavioural tests, survival analyses, immunohistochemical investigations and electrophysiology. If successful, we will determine the primary pathogenic consequences of inhibitory insufficiency in ALS, and how this varies in different neuronal compartments. In doing so we will identify critical intervention points in the disease process. Funded by: Motor Neurone Disease Research Australia - Grant - Innovator ($99,809); University of Tasmania.

Project Total: $235,000; Funding support for HDR student project costs for students working in the Dickson and Blizzard labs on Neurodegenerative diseases. Funded by: Masonic Medical Research Foundation Limited ($235,000); University of Tasmania.

Project Total: $115,688; New therapeutic targets are required for ALS. To interrogate the role of individual cell types and thus reveal these targets, we need to selectively affect subpopulations of cells that exist within larger heterogeneous cell networks with complex connections. Critical subpopulations include cells from discrete anatomical regions (brain and spinal cord) and specific types of cells (cortical and spinal MNs, Interneurons and glia) all with specific and defined connections. Independently manipulating these subpopulations in a traditional primary culture preparation, or even within an organoid model, is impossible. We will overcome this limitation by developing, validating and using a customised microfluidic primary cell culture platform. Funded by: FightMND ($260,688); University of Tasmania.

Project Total: $100,000; The Olympus VS200 Research Slide Scanner enables the imaging of entire tissue sections in an automated manner. It can acquire images from up to six fluorescent channels along with brightfield, dark field and phase contrast, and has objectives up to 100X. The robotic slide loader allows for batch scanning of up to 210 slides at a time and can accommodate multiple sizes of slides up to 4?x5? plates for large tissue sections. Our current VS120 slide scanner is already used at a maximum capacity with researchers having to book weeks in advance to scan slides. The VS200 will add further capacity and offers improved capabilities with greater optical resolution, more fluorescent channels, more batch scanning capacity and the ability to scan larger slides. Pairing this with free open source software like QuPath provides high throughput, efficient and highly accurate quantitative workflows that greatly improve productivity. Funded by: Ian Potter Foundation - Grant - Medical Research ($100,000); University of Tasmania.

Project Total: $98,339; Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal late onset motor neuron disease for which there are currently no effective treatments or cure. Development of effective therapeutics for ALS is complicated by the fact that it shows substantial clinical heterogeneity, with a high degree of variability in susceptibility, site of onset of symptoms, age of onset, and severity and progression of disease. However, what underpins this heterogeneity is not understood. Here we will utilise a unique cohort of human tissue, alongside highly characterised transgenic model tissue, to investigate the role of individual glial populations in triggering inhibitory pathogenesis. The findings of this project will contribute important knowledge to the problem of clinical heterogeneity in ALS, and prove invaluable for the development of therapeutic candidates that can be targeted to the motor system during the symptomatic phase. Funded by: Motor Neurone Disease Research Australia - Grant - Innovator ($98,339); University of Tasmania.

Project Total: $624,821; Amyotrophic lateral sclerosis (ALS) is an unrelenting and fatal disease in which motor neurons of the motor cortex and spinal cord rapidly degenerate. One of the earliest detectable clinical markers of ALS is hyperexcitability. We have discovered that upper motor neurons in the motor cortex and lower motor neurons in the spinal cord, may be differentially vulnerable to pathogenic effects of hyperexcitability, and possibly the resulting excitotoxicity. Furthermore we have evidence to suggest that age and sex, two important patient demographic variables in ALS also may influence the vulnerability of motor neurons to excitotoxicity. This indicates that a blanket treatment approach toward excitotoxicity in ALS may not be appropriate for the protection of all motor neurons. An innovative and potentially more effective strategy is to specifically tailor treatment to the differential changes that are occurring in the brain and spinal cord through disease progression. With leading-edge experimental design in appropriate models this project will determine how age and sex impacts excitotoxicity in mouse models of ALS (Aim 1), if upper and lower motor neurons are differentially vulnerable to disease using mouse models and patient derived induced pluripotent stem cells (Aim 2) and whether diffuse sub-threshold transcranial magnetic stimulation, a non-invasive form of central nervous system network stimulation, can regionally treat upper and lower motor neurons to halt disease progression in mouse models of ALS (Aim 3). This project brings together a team of CIs and AIs that have a demonstrated excellence in all aspects necessary for this project. The CI team (Catherine Blizzard and Tracey Dickson) have a long and productive collaborative track record; 29 publications and $3.5 million in funding together. This is the first time a disease treatment has been trialled in ALS that applies approaches tailored to address pathology in distinct regions of the corticomotor system. Funded by: National Health & Medical Research CouncilNational Health & Medical Research Council - Grant-Ideas ($1,249,642); University of Tasmania.

Project Total: $534,837; There is no cure for Parkinson's disease (PD). Current treatments target only mid- to late-stage symptoms of the disease, with poor long-term efficacy and high risk of debilitating side-effects. Research by our CI team suggests that glia, the non-neuronal? cells in the central nervous system (CNS), may play a critical yet unappreciated role in the progress of PD. We have found roles for glial cells in modifying the neuronal environment and promoting a domino-like spread of abnormal alpha-synuclein (-syn), the major protein implicated in PD pathology, and in spreading functional changes through CNS networks. These data point to central roles for glial cells in propagating pathological changes between susceptible neuron populations. We will now apply novel in vitro and in vivo models to test the central hypothesis Glial cells facilitate the spread of pathology through the central nervous system in PD? to find ways to stop the disease processes earlier. Our research has two aims: AIM 1: Determine the role of glial cells in the neuron-to-neuron transfer of -syn and the spread of associated pathological changes. Using customised microfluidic cell culture platforms developed by the CI team, we will systematically interrogate the role of specific glial cell subtypes and inflammatory processes in the pathogenic mis-folding of -syn and its cell-to-cell transfer. AIM 2: Determine the role of glial cell activation on -syn transmission and the spreading of PD pathology using an in vivo model of progressive PD. We will test the hypothesis that inflammatory functions of glial cells and -syn interact to cause PD pathology to progress through CNS networks. The outcomes will determine the individual and synergistic roles of -syn and glial cells in the degeneration of PD-vulnerable neurons. This study will redefine our understanding of pathological processes in PD, thereby exposing new targets for development of better treatments. Funded by: National Health & Medical Research CouncilNational Health & Medical Research Council - Grant-Ideas ($1,069,674); University of Tasmania.

Project Total: $545,563; The critical importance of understanding how the brain functions is evidenced by international investment in this area of research. For example, in the US, BRAIN (Brain Research through Advancing Innovative Neurotechnologies) has been supported with $1-3 billion, while in Europe the 'Human Brain Project' is supported with $1.5 billion. This proposal falls directly within the scope of these with its focus on new platform technology to underpin fundamental molecular studies of neuronal circuits. It is in the national interest of Australia to undertake internationally leading cross-disciplinary research in this area, a position confirmed in the Academy of Science coordinated Think Tank on Inspiring smarter brain research in Australia?. Being the first to develop this new platform technology, will allow Australian researchers to be at the forefront of determining the mechanisms underlying neurodegenerative diseases, and the development of new treatments. In addition, direct financial benefit could be obtained through the technology, for example, through licensing novel microchamber designs. Funded by: Australian Research Council - Grant-Discovery Projects ($545,563); University of Tasmania ($109,282).

Project Total: $15,000; Currently there are few treatments available to motor neuron disease patients, which provide substantial improvement in lifespan and quality of life. Previously therapies have focused on improving motor neuron pathology. However, in amyotrophic lateral sclerosis (ALS), inhibitory network activity which is vital for supporting motor neuron function is dysfunctional. Through the use of mouse models and induced-motor neurons, interneurons and glia derived from patient cells, this project aims to understand how inhibitory interneurons can be used as a therapy to improve motor neuron health in ALS. Funded by: Motor Neurone Disease Research Australia - Scholarship-PhD Top-Up Grant ($15,000); University of Tasmania.

Project Total: $140,660; We will perform a narrative literature review relevant to project. We will test the potential of cannabinoids to treat or hinder the progression of neurodegenerative conditions and brain injury, using relevant cell-culture based models. The specific experiments will be informed and designed based on outcomes from an extensive literature review (included in our research). We will employ a number of primary cell-culture models, in which the pathogenic processes of specific neurodegenerative diseases are mimicked by alteration of the extracellular environment. These models reproduce pathological changes in neurons that occur in disease and reflect specific aspects of the disease processes, and will test the potential of cannabinoids to reverser or slow these changes. We will assess specific and disease-relevant outcomes pertaining to neuronal functions and morphology. Results will be delivered in report format. Funded by: Cyrelian ($140,660); University of Tasmania.

Project Total: $50,000; This Tasmanian proposal Lead by Professor Tracey Dickson, from the Menzies Institute for Medical research will leverage off her national and internationally leading MND research and the work that she has pioneered over the last ten years done developing novel microfluidic platforms for modelling circuits of the Central Nervous System. Professor Dickson's group has a unique capability to develop both Lower Motor Neuron and Upper Motor Neuron circuits - _'on a chip'. Ultimately these platforms will serve as important drug screening assays for MND, for testing hypotheses beyond individual cells types. Funded by: FightMND ($50,000); University of Tasmania.

Project Total: $997,046; We will test an HDAC6 inhibitor in models of ALS. We will investigate the HDA6 inhibitor activity of novel compounds Funded by: FightMND - Grant - Drug Development Grant ($997,046); University of Tasmania.

Project Total: $175,000; Funded by: University of Tasmania - Grant-Research Enhancement Program; University of Tasmania ($198,791).

Project Total: $99,700; Deficits in neuroplasticity may be one of the earliest events in Frontotemporal Dementia (FTD). Our studies have identified that TDP-43, a frequently aggregated protein in FTD specifically affects neuroplasticity at the dendrite spine in mouse models of FTD. Furthermore we have identified that this pathogenic mechanism is likely due to the translocation of TDP-43 into the cytoplasm. It is now time to unravel the role of mislocalised TDP-43 in neuroplasticity deficits that may drive FTD and perform vital pilot investigations to determine if we can modulate these circuitry deficits non-invasively using transcranial magnetic stimulation (TMS). We will address the hypothesis: 'Neuroplasticity deficits are an early disease causing event in FTD that can be modulated with TMS' using novel mouse models and multiphoton live imaging. This project will be lead by Dr Catherine Blizzard in conjunction with Dr Kaylene Young, who will strategically use the Dementia Australia funding to unravel the earliest changes in neuroplasticity that may drive FTD and generate the pilot data necessary to provide evidence for a large-scale pre clinical trial investigating novel ways to ameliorate neuroplasticity deficits that characterises FTD Funded by: Motor Neurone Disease Research Australia - Grant - Innovator ($99,700); University of Tasmania.

Project Total: $75,000; Deficits in neuroplasticity may be one of the earliest events in Frontotemporal Dementia (FTD). Our studies have identified that TDP-43, a frequently aggregated protein in FTD specifically affects neuroplasticity at the dendrite spine in mouse models of FTD. Furthermore we have identified that this pathogenic mechanism is likely due to the translocation of TDP-43 into the cytoplasm. It is now time to unravel the role of mislocalised TDP-43 in neuroplasticity deficits that may drive FTD and perform vital pilot investigations to determine if we can modulate these circuitry deficits non-invasively using transcranial magnetic stimulation (TMS). We will address the hypothesis: 'Neuroplasticity deficits are an early disease causing event in FTD that can be modulated with TMS' using novel mouse models and multiphoton live imaging. This project will be lead by Dr Catherine Blizzard in conjunction with Dr Kaylene Young, who will strategically use the Dementia Australia funding to unravel the earliest changes in neuroplasticity that may drive FTD and generate the pilot data necessary to provide evidence for a large-scale pre clinical trial investigating novel ways to ameliorate neuroplasticity deficits that characterises FTD. Funded by: Dementia Australia Research Foundation Ltd - Grant-Project Grants ($75,000); University of Tasmania.

Project Total: $1,700,000; This proposal is for strategic and specialised equipment underpinned by basic infrastructure required to support neurodegenerative disease research within the CHM. Funded by: University of Tasmania; University of Tasmania.

Project Total: $173,250; Funded by: University of Tasmania - Grant- Research Enhancement Program; University of Tasmania ($173,250).

Project Total: $10,186; Too much of a 'good thing' can be bad, especially when it comes to the brain. Glutamate is an important signalling molecule that allows nerves to talk to each other, but it can be toxic if too much is present. The brain has protective machinery in place to move glutamate into cells where it can be detoxified?, but if this transport machinery fails, the brain can be damaged. People with multiple sclerosis (MS) have abnormally high levels of glutamate outside of brain cells, both within brain lesions and in seemingly healthy parts of the brain. Dysfunction of the glutamate uptake machinery may be responsible, or at the very least contribute to higher glutamate levels and cause further damage in MS. However, we currently know very little about the levels of the glutamate uptake machinery in healthy people. The main aim of this project will be to examine glutamate uptake machinery in the brains of healthy people, in order to establish appropriate background data so that this information will be available for future studies in MS brain. In addition, I will undertake some studies in mouse brain, to determine if this would be an appropriate model for future MS studies. Funded by: University of Tasmania - Grant- Research Enhancement Program; University of Tasmania ($10,186).

Project Total: $936,572; Motor Neuron Disease (MND) is a rapidly progressing neurodegenerative disease. There are no cures and no effective treatments for MND, with people diagnosed having a median survival of only three years from symptom onset. Not knowing the cause of MND or how it progresses through the CNS have been immense barriers to the development of effective therapeutics. We have reached a critical time in MND research. Our research team has been dedicated to researching the mechanism of MND for the last ten years. We are now poised to transition my teams research efforts from determining the cause of this disease to using this knowledge to develop treatments. A critical pathway that our work and others have shown is key to MND is altered network excitability and subsequent excitotoxicity in the cortex. We have recent published and preliminary data that identifies that a critical potential point of intervention in this pathway is via the subclass of inhibitory cells that express neuropeptide Y (NPY). The overarching Aim for this Cure for MND Translational Research Grant is to now target this pathway to develop a treatment. By performing this world-first preclinical trial we will reveal further aspects of disease pathogenesis. Positive outcomes from these trials will identify a candidate compounds for progression to a human trial for the treatment of MND. Funded by: FightMND - Grant-Translational Research Grant ($936,572); University of Tasmania ($50,000).

Project Total: $547,857; The ability to form and recall memories is a fundamental function of the brain. This ability is affected by neurodegenerative diseases such as Alzheimer's Disease. This project will uncover the regulatory framework that defines the brain cells involved in forming memories, and how these change during Alzheimer's Disease progression. Funded by: National Health & Medical Research CouncilNational Health & Medical Research Council - Grant-Project ($1,095,714); University of Tasmania.

Project Total: $38,250; TBA by Institute Funded by: University of Tasmania - Grant- Research Enhancement Program; University of Tasmania ($38,250).

Project Total: $4,000,000; To assist the Recipient to undertake research and collaboration activities to deliver healthier, longer and better lives for Tasmanians and to assist the Recipient to undertake such activities by financially supporting medical research fellowships. These fellowships aim to ensure long-term support for recruitment and retention of a high-quality, and highly skilled, medical research workforce, including through an ability to recruit skilled migrants, growing the medical research industry and optimizing associated positive contributions to the Tasmanian economy. Funded by: Department of State Growth (Tas) - Grant ($4,500,000); University of Tasmania.

Project Total: $99,767; Amyotrophic Lateral Sclerosis (ALS) is incurable, caused by the death of motor neurons in the cortex and spinal cord. There is a desperate need to discover new therapeutic ways to stop this neuron death, ideally targeted at early changes in the disease to prevent the majority of cell loss. There is growing evidence that neuronal dysfunction in the cortex is occurring in ALS well before symptoms present. Disturbances in neuronal synapses may be one such early event that potentially leads to neuronal dysfunction and then death. Changes in synapses can have serious effects on neurons' activity levels and if not controlled can cause neuron death. The RNA binding protein TDP-43 is likely to play a critical role in ALS as inappropriate localization of this protein is frequent in the disease and mutations in TDP-43 causes a genetic form of ALS. We have found that TDP-43 involved in maintaining synapses between neurons; regulating the number and maturation of spines. It is feasible that an early disease-causing event in ALS may be changes to synapses. We will investigate how different mutations of the TDP-43 protein determine the number and composition of spines as it happens in upper motor neurons of the cortex. This novel research program addresses an important gap in the current understanding of how synaptic changes can lead to neuron death in ALS and may open up a new target for drug intervention in this devastating disease. Funded by: Motor Neurone Disease Research Australia - Grant-In-Aid ($99,767); University of Tasmania.

Project Total: $250,000; Donation to Tracey Dickson and group for the purchase of a confocal microscope Funded by: The Select Foundation - Donation ($250,000); University of Tasmania.