The research of my group focuses on understanding the signalling events that are triggered by activity, and their impact on neuronal survival and death.
In central neurons, Ca2+ entry through the NMDA-type glutamate receptor (NMDAR) is a major source of synaptically-evoked Ca2+ transients and directly affects neuronal survival/death: while too much NMDAR activity is harmful, so is too little (Hardingham and Bading, 2003; Papadia and Hardingham, 2007).
Understanding the mechanisms behind this dichotomous signalling is an area of molecular neuroscience with direct clinical implications.
The research of my group focuses on understanding the signalling events that are triggered by NMDAR activity, and their impact on neuronal survival and death, and comprise three main themes.
Physiological patterns of synaptic NMDAR activity are strongly neuroprotective, the basis for which is unclear.
Synaptic NMDAR activity induces signalling pathways which activate new gene expression as well as triggering the post-translational modification of existing proteins.
We aim to understand the molecular events that underlie activity-dependent neuroprotection, including the role of gene expression changes.
An understanding of the brain's natural "neuroprotective" mechanisms is important, since malfunction of these mechanisms may contribute to neurodegeneration in a variety of debilitating brain disorders (Alzheimer's, ALS, Huntington's, Parkinson's), and also neurodevelopmental disorders associated with NMDA receptor inhibition (such as Foetal Alcohol Syndrome).
Intrinsic antioxidant defences are important for neuronal longevity. However, little is known about whether they are subject to dynamic regulation, or are a fixed function of neuronal type/age.
This is an important question: any regulation could influence biological ageing, or progression of neurodegenerative disorders associated with oxidative damage.
We are studying the influence of synaptic NMDAR activity on antioxidant enzymic systems and how it influences the vulnerability of neurons to oxidative insults.
This theme is aimed at understanding what parameters determine whether an episode of NMDAR activity promotes neuroprotection, or cell death, other than simply the magnitude of Ca2+ influx.
We are examining the relative importance of NR2 subunit composition, PDZ protein interactions, synaptic vs. extrasynaptic location and spatial calcium dynamics in influencing survival/death following NMDAR activation.
We employ a large array of techniques to realise our research aims. Gene regulation programmes are analysed by expression analysis (Genechip), RT-PCR and chromatin-IP.
The role of individual genes is probed by siRNA and over-expression studies, while NMDAR signalling is studied via an array of electrophysiological, live-cell imaging techniques, and second messenger assays.
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This article was published on Aug 6, 2012