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Neuregulin 1 Type III Overexpression And Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$651,966.00
Summary
Neuregulin (NRG1) is a neuronal growth factor and regulates the development of cortical inhibitory interneurons. Human studies suggest that NRG1 type III overexpression and deficient interneuron development underlie schizophrenia. Thus, we have developed a mouse overexpressing Nrg1 type III to discover mechanisms behind NRG1-related cortical pathology and schizophrenia-like behaviours and to clarify whether NRG1 type III interacts with environmental risk factors for the disorder.
ARX- A Hub Gene For A Common Biological Pathway In Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$707,974.00
Summary
Schizophrenia is a severe psychiatric disorder with no cure. I have identified that some people with schizophrenia show variations to a gene called ARX. This project will use preclinical mouse models to explore how variations to the Arx gene affect brain molecules, networks of cells and behavioural outcomes. This biological pathway will provide the framework for the identification of new molecules to target therapeutically to modify the biological course of schizophrenia and improve outcomes.
Using Artificial Synapses To Investigate The Functional Pathology Underlying Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$515,256.00
Summary
Epilepsy is a common neurological disorder. Some forms arise from hereditary mutations to GABA-A receptors. To advance our understanding of epileptogenesis, it is necessary to understand how mutations affect GABA-AR function. We will use a novel ‘artificial synapse’ system to characterise these mutant receptors. This will define how epilepsy is caused and inform us how to best tailor drug treatments for different epilepsy conditions.
Oxytocin As A Novel Antagonist Of The Intoxicating And Addictive Effects Of Alcohol
Funder
National Health and Medical Research Council
Funding Amount
$739,106.00
Summary
Alcohol is Australia’s most harmful recreational drug and more effective treatments for alcohol abuse are desperately needed. The CIs have shown that administering oxytocin reduces alcohol intoxication and consumption, and prevents alcohol from acting at specific sites in the brain that are central to alcohol’s intoxicating and addictive effects. This project probes the effects of oxytocin at these sites and the potential utility of targeting this interaction to treat alcohol-use disorders.
Modifying Brain Excitabilty By Upregulating The KCC2 Chloride Transporter
Funder
National Health and Medical Research Council
Funding Amount
$535,662.00
Summary
Brain activity depends upon the fine balance between neuronal excitation and inhibition. When this balance is lost, debilitating seizures can result, such as occurs in epilepsy. We have developed a new gene manipulation approach to enhance neuronal inhibition and prevent seizures in mice. We will examine the physiological mechanisms underlying this effect, and we propose that we can also use this genetic switch to stop the progression into epilepsy that occurs following a brain trauma.
Delta-containing GABA-A Receptors As Targets For Neuroprotection
Funder
National Health and Medical Research Council
Funding Amount
$953,825.00
Summary
After stroke, the neurotransmitter, GABA spills onto sites located away from the synapse. This spillover is hypothesised to have a protective role in limiting cell death. However the timeframe for this to occur is too long for observing significant beneficial effects after stroke. Therefore, stimulating this naturally occurring protective mechanism early using pharmaceutical interventions that target a specific type of GABAA receptor is an unexplored strategy to minimize cell death after stroke.
Preclinical Assessment Of The Potential Utility Of Oxytocin And A Novel Oxytocin Agonist For The Treatment Of Substance Use Disorders And Social Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$320,891.00
Summary
Recent work has highlighted the utility of stimulating the brain oxytocin (OT) system in the treatment of numerous psychiatric disorders, in particular substance use disorders and social disorders (e.g. autism). I will focus on the continuation of two interrelated projects during my Fellowship: (1) preclinical exploration of OT as a novel treatment for alcohol use disorders; and (2) further developing our novel non-peptide OT agonist (SOC-1), which has profound pro-social effects.
The Alpha5 GABA-A Receptor: Delineating An Emerging Therapeutic Target
Funder
National Health and Medical Research Council
Funding Amount
$481,178.00
Summary
GABA-A receptors mediate inhibitory synaptic transmission in the brain. Receptors containing ?5 subunits are therapeutic targets for many neurological disorders. We aim to characterise the functional properties of the main ?5-containing isoforms using high-resolution imaging and whole-cell recording. Our goal is to understand which ?5-containing isoform should be preferentially targeted (and how) when seeking to treat the various disorders in which these receptors have been implicated.
?4-containing GABA-A Receptors As Targets For ?-hydroxybutyric Acid (GHB)
Funder
National Health and Medical Research Council
Funding Amount
$610,572.00
Summary
?-Hydroxybutyric acid (GHB) is an elusive substance. On one hand, it is a prescribed drug to treat narcolepsy, and ameliorate alcohol withdrawal. On the other hand, GHB is the club drug “Fantasy” or “Liquid Ecstasy”, taken by many Australians for its social, sexual and euphoric effects. This proposal will identify GHB targets and provide insight to its mechanism of action.
A Novel Mechanism For Therapeutically Modulating Neurotransmitter-activated Ion Channels
Funder
National Health and Medical Research Council
Funding Amount
$667,529.00
Summary
This project aims to elucidate the mechanisms by which macrocyclic lactones bind to brain ion channel receptors. This will reveal fundamental new insights into the operation of these receptors and will have important implications for the design of novel treatments for a variety of central nervous system disorders.