Assessing The Role Of The N-terminus Of The Prion Protein, Emphasising Constitutive Cleavage, In Normal Function And Pathogenesis, As Well As Defining The Relationship Between Intensity Of Surveillance And Sporadic CJD Incidence.
Funder
National Health and Medical Research Council
Funding Amount
$387,469.00
Summary
As a neurologist undertaking research into prion diseases over an extended period, I have been able to lead and participate in many projects that have made significant contributions, such as validation of new diagnostic tests for Creutzfeldt-Jakob disease (CJD), assessment of potential therapeutics, provide insights into the normal function of the prion protein and the underlying pathways causing cellular damage and determine the real significance of apparent clusters of sporadic CJD.
The Role Of Down Syndrome Candidate Region 1 (DSCR1) In Neurotransmitter Release, Vesicle Recycling And Down Syndrome.
Funder
National Health and Medical Research Council
Funding Amount
$352,318.00
Summary
Individuals with Down syndrome (DS) have three copies of human chromosome 21 (HSA21), rather than the normal two. The symptoms observed in DS individuals are therefore due to the overexpression of HSA21 genes. Since all individuals with DS develop symptoms in the brain similar to those see in Alzheimer's disease (AD), there may be a common mechanism that can be traced to the extra gene dosage from HSA21. We are interested in one of these genes, Down syndrome candidate region 1 (Dscr1), which is ....Individuals with Down syndrome (DS) have three copies of human chromosome 21 (HSA21), rather than the normal two. The symptoms observed in DS individuals are therefore due to the overexpression of HSA21 genes. Since all individuals with DS develop symptoms in the brain similar to those see in Alzheimer's disease (AD), there may be a common mechanism that can be traced to the extra gene dosage from HSA21. We are interested in one of these genes, Down syndrome candidate region 1 (Dscr1), which is overexpressed in both DS and AD brains. We hypothesise that Dscr1 has a role in regulating exocytosis, a process in which chemical messengers are released from cells. Exocytosis is highly specialised in the brain where neurotransmitters are released from neuronal synapses in a process known as synaptic transmission. Reduced synaptic transmission is one of the earliest hallmark of DS and AD occurring long before the classical neurological traits of DS and AD such as plaque formation and dementia. We propose that alterations in Dscr1 expression are responsible for the reduced neuronal exocytosis observed in the early stages of DS and AD. We have generated mice in which Dscr1 expression is altered, as occurs in DS and AD brains, and our preliminary studies indicate that exocytosis is reduced in these mice. We now wish to find the intracellular changes responsible for regulating exocytosis when Dscr1 expression is altered. We also aim to compare this to exocytosis in classical DS mouse models which have an extra chromosome 21 and in similar DS mouse models which have normal levels of Dscr1. This project will uncover the currently unknown functions of Dscr1 in exocytosis in an animal model, allow us to gauge whether Dscr1 is solely responsible for altering exocytosis in DS amongst other HSA21 genes, enable us to better understand the mechanisms initiating DS and AD and possibly lead to new targets of early intervention in these diseases.Read moreRead less
Astrocyte-Neuron Communication: Unravelling The Role Of Astrocytes In The Modulation Of Neuronal Circuits
Funder
National Health and Medical Research Council
Funding Amount
$403,064.00
Summary
Astrocytes, a type of glial cell, are the most numerous cell type in the brain. They outnumber their neuronal counterparts by ten times and make up almost 90% of adult brain weight. They were originally thought to have only a supportive role in brain metabolism and the regulation of brain blood flow. It is now known that they also modulate neurons and their synapses through release of vesicles containing specific substances and have key roles in some neuropathic (e.g. pain and epilepsy) and neur ....Astrocytes, a type of glial cell, are the most numerous cell type in the brain. They outnumber their neuronal counterparts by ten times and make up almost 90% of adult brain weight. They were originally thought to have only a supportive role in brain metabolism and the regulation of brain blood flow. It is now known that they also modulate neurons and their synapses through release of vesicles containing specific substances and have key roles in some neuropathic (e.g. pain and epilepsy) and neurodegenerative states (e.g. Alzheimer's disease, Parkinson's disease, and multiple sclerosis). Many of these diseases are associated with a pathological astrocyte process known as 'reactivity'. This process remains enigmatic, resulting in so-called reactive gliosis, a reaction characterized by changes in gene expression, cell enlargement and changes in cell shape, and, in some cases, cell division. Most of the research on astrocyte reactivity has focused on the impairment of astrocyte metabolic activities. Comparatively little is known about the effect of reactive gliosis on so called 'newer' astrocyte roles such as their ability to interact with each other and nearby neurons using exocytosis of gliotransmitters (GTs: glutamate and ATP) and neurotrophic factors (NTFs: glial and brain derived neurotrophic factors). This project will both further investigate the normal mechanisms of astrocyte-neuron communication, and examine the effects of astrocyte reactivity on these mechanisms. The aim is to identify possible therapeutic targets to ameliorate the detrimental affects of neurodegeneration.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE200100029
Funder
Australian Research Council
Funding Amount
$700,000.00
Summary
High Resolution PET-CT for Small Animal Molecular and Anatomical Imaging. This project will integrate a next generation small animal PET-CT instrument into the Sydney Imaging multi-modality imaging ecosystem. PET-CT enables the investigation of molecular function and anatomical structure in complex living organisms. This platform will enable research as diverse as the development and in-vivo characterisation of new chemical probes and nanoparticles that bind to specific protein targets in the bo ....High Resolution PET-CT for Small Animal Molecular and Anatomical Imaging. This project will integrate a next generation small animal PET-CT instrument into the Sydney Imaging multi-modality imaging ecosystem. PET-CT enables the investigation of molecular function and anatomical structure in complex living organisms. This platform will enable research as diverse as the development and in-vivo characterisation of new chemical probes and nanoparticles that bind to specific protein targets in the body, investigating mechanisms of brain plasticity in predictive learning, understanding the molecular pathways involved in neurodegeneration and cancer, developing novel methods for multi-modal image analysis, and developing and validating new radiation detectors for the next generation of imaging technology.Read moreRead less
The role of P2X7 and P2X4 receptor mediated innate phagocytosis in pathogenesis and treatment of neurodegenerative diseases. This project will identify how inherited variation in two proteins of the brain can accelerate the removal of neurones and predispose to a range of neurodegenerative diseases. Knowledge of the biological basis of this finding will allow a search for new compounds which will slow and protect against this form of neurodegeneration.
Physiology of tau protein: a novel role in scaffolding and intracellular distribution. Understanding brain function remains a challenge. This project will study the normal role of the Alzheimer's disease-related protein tau in brain function during ageing. This will significantly enhance current understanding of brain function.
Thalamocortical Neural Circuits In Higher Order Cognitive And Sensory Processing
Funder
National Health and Medical Research Council
Funding Amount
$370,860.00
Summary
Schizophrenia, depression and dementia are devastating disorders with problems in thinking and sensory perception, but the neural circuits causing these symptoms are not known. I will use new optical and genetic tools in mice to identify the cortical and subcortical circuits required for complex touchscreen tasks, the same tasks to assess patients. Identification of neural circuits that underlie clinical symptoms will increase our understanding of these disorders and improve treatments.
Interaction Of Amyloid-beta And Tau Pathology In Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$122,592.00
Summary
Currently, over 200,000 Australians are affected by Alzheimer's disease (AD) and related forms of dementia, causing a huge socio-economic damage. To overcome the lack of effective treatments, we need to understand the underlying causes and translate them into therapy. Using state-of-the-art cell culture and genetic mouse models, I will reveal fundamental processes in AD and related dementias, and develop tailored treatments to battle these devastating disorders.
Psychosis contributes significantly to global disease burden, affecting more than 3% of the population when schizophrenia, schizoaffective disorder, and bipolar disorders are considered together. These conditions aggregate within families, and genetic risk factors do not conform to traditional diagnostic categories. My work employs brain-based classification techniques to derive subtypes of psychosis that dissect, and/or span the diagnostic categories, for investigation of modifiable genetic and ....Psychosis contributes significantly to global disease burden, affecting more than 3% of the population when schizophrenia, schizoaffective disorder, and bipolar disorders are considered together. These conditions aggregate within families, and genetic risk factors do not conform to traditional diagnostic categories. My work employs brain-based classification techniques to derive subtypes of psychosis that dissect, and/or span the diagnostic categories, for investigation of modifiable genetic and environmental risk factors for psychosis.Read moreRead less
Functional Genomics Approach To Extend Lifespan While Preventing Age-related Cognitive Decline
Funder
National Health and Medical Research Council
Funding Amount
$772,600.00
Summary
In our ageing population, preventing age-related neurological decline is one of the central medical challenges of the 21st century. Here we use human population data obtained from people who reached 90 years of age free of any disease, or patients who suffer from dementia, combined with functional genomics studies in animals to pinpoint new genes that can be targeted to extend lifespan while preserving neurological function in these extended years of life.