Elucidating The Mechanisms Of Alpha-conotoxin-induced Calcium Channel Inhibition Via G Protein-coupled Receptors
Funder
National Health and Medical Research Council
Funding Amount
$419,082.00
Summary
N-type voltage-gated calcium channels (VGCCs) are membrane proteins involved in neurotransmission and play a major role in pain. VGCCs are a well-established target for the development of analgesics. Our recent research identified that VGCCs can be inhibited by ?-conotoxins from the venom of marine snails by targeting ?-aminobutyric acid receptors in sensory neurons. We will characterize this novel form of modulation of VGCCs by ?-conotoxins and define the pathways that lead to VGCC inhibition.
Unveiling the nanoscale organisation and dynamics of synaptic vesicle pools. This project aims to uncover the role of key molecules in allowing brain cells to actively communicate with each other. Communication between neurons relies on the fusion of synaptic vesicles containing neurotransmitters with the presynaptic plasma membrane. The addition of vesicular membrane is transient as the vesicles quickly reform from the plasma membrane and refill with neurotransmitter ready for subsequent rounds ....Unveiling the nanoscale organisation and dynamics of synaptic vesicle pools. This project aims to uncover the role of key molecules in allowing brain cells to actively communicate with each other. Communication between neurons relies on the fusion of synaptic vesicles containing neurotransmitters with the presynaptic plasma membrane. The addition of vesicular membrane is transient as the vesicles quickly reform from the plasma membrane and refill with neurotransmitter ready for subsequent rounds of fusion. This recycling process ensures that neurons communicate efficiently, however the underpinning mechanism is unknown. This project aims to use a recently developed single synaptic vesicle super-resolution tracking method to establish how Myosin-VI and Synapsin-IIa orchestrate this recycling in central and peripheral neurons. It will explain how neurons manage to preserve their ability to communicate.Read moreRead less
Role Of The Microglial Adaptor Molecule TYROBP In Alzheimer’s Disease Pathology
Funder
National Health and Medical Research Council
Funding Amount
$469,433.00
Summary
Immune activation characterizes Alzheimer’s disease (AD) brains; however, how it impacts AD progression is not understood. Our previous studies in AD brains identified the immune molecule TYROBP, pointing at both beneficial and detrimental effects triggered by this molecule. Here, we aim to understand in detail how TYROBP is involved in AD and how we can enhance its beneficial effects and decrease its unintended actions.
Targeting Post-synaptic Tau To Treat Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,686,311.00
Summary
We have previously identified post-synaptic tau as being critical in mediating toxicity in Alzheimer's disease brains. This project aims at understanding the exact underlying molecular mechanisms and, more importantly, developing novel drugs to block early toxicity that initiates cascades that eventually lead to brain atrophy and dementia. To achieve this aim, this project will generate and utilize models of Alzheimer's disease in combination with a broad range of latest analytical tools.
Interactions Between Developmental NMDA Receptor Dysfunction, Genetic Vulnerability And Early-life Stress In Schizophrenia: Studies Of Dysbindin Mutant Mice And Living Individuals At High Risk Of Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$347,457.00
Summary
This project will investigate two key pathways implicated in schizophrenia: glutamatergic (excitatory) neurotransmission and stress signalling. We will study how glutamatergic deficits emerge across postnatal development, in the presence or absence of early-life stress, in a schizophrenia-relevant mouse model, and investigate the interactions between stress and glutamatergic deficits in neuroepithelial cells from living individuals at high risk of schizophrenia.
Regulation Of Glutamate Receptor Trafficking By The Calcium- And Lipid-binding Protein, Copine-6
Funder
National Health and Medical Research Council
Funding Amount
$548,690.00
Summary
Abnormal levels of cell surface receptors in neurons can lead to a variety of debilitating neurological disorders and neurodegenerative diseases. These levels are tightly regulated through the orchestrated movements of receptors from inside the neuron to the cell surface. In this project we will examine how the transport of cell surface receptors is regulated by an intracellular signalling molecule, called copine, which is important in both epilepsy and Alzheimer’s disease.
Experience-dependent Cellular Plasticity And Cognitive Deficits In Mouse Models Of Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$444,318.00
Summary
Schizophrenia is a brain disorder involving psychiatric symptoms which include abnormalities of cognitive processes. We are using mouse models to understand the cause of cognitive deficits, at the level of molecules and cells. One discovery we have made is that the generation of new neurons, from adult neural stem cells, are abnormal in a specific brain region of these mice. This research will provide new information regarding the cause of cognitive deficits, and will have implications for the d ....Schizophrenia is a brain disorder involving psychiatric symptoms which include abnormalities of cognitive processes. We are using mouse models to understand the cause of cognitive deficits, at the level of molecules and cells. One discovery we have made is that the generation of new neurons, from adult neural stem cells, are abnormal in a specific brain region of these mice. This research will provide new information regarding the cause of cognitive deficits, and will have implications for the development of new treatments.Read moreRead less
Targeting The Synaptic Actin Cytoskeleton In Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$840,741.00
Summary
Dementias have become one of the fastest growing sources of major disease burdens in developed countries with about one in fifteen Australians older than 65 being affected. We will study how pathological stimuli disrupt nerve cell connections in the brain by impacting on the cellular architecture at these connections. Findings from our study will provide profound new insights in how nerve cells communicate with each other and how this communication is breaking down in disease.
Lysosomal Dysfunction As An Inhibitor Of Vitamin B12 Utilisation In Neurodegenerative Diseases
Funder
National Health and Medical Research Council
Funding Amount
$554,901.00
Summary
Vitamin B12 is required for red blood cell formation, DNA synthesis and normal neurological function. B12 deficiency contributes to age-related cognitive decline and Alzheimer’s disease. This research will provide important new information regarding the ageing process and the impact that brain changes associated with ageing and Alzheimer's disease have on B12 metabolism. It will provide important information related to the therapeutic potential of B12.
The Impact Of The Changes In Levels Of Adhesion Molecules NCAM2 And DsCAM On Synapse Formation And Function: Implications For Down Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$334,053.00
Summary
Down syndrome (DS) results from triplication of chromosome 21 and leads to mental retardation, molecular mechanisms of which are not understood. We found that two proteins, NCAM2 and DSCAM, encoded at chromosome 21 are highly expressed in synapses. Synapses are specialized contacts between neurons which allow neurons to process information in the brain. In this project we will test a hypothesis that changes in NCAM2 and DSCAM expression result in synapse abnormalities observed in DS.