The mechanism of long-lasting activity-dependent neuroprotection. (360G-Wellcome-078178_Z_05_Z)

£265,087

Several factors regulate neuronal survival during development and maturity. One important mechanism involves activity-dependent signalling through synaptic NMDA receptors (NMDARs), though the mechanism is poorly understood. We recently showed that synaptic NMDAR-dependent neuroprotection comprises twodistinct phases: 1.Acute protection triggered by continuous activity, mediatedby the PI3K-Akt pathway. 2.A novel long-lasting or 'late-phase' of neuroprotection that extends long after activity has ceased ( > 60 hrs), which is dependent on transcription mediated by the cAMP response element (CRE) binding protein (CREB) family of transcription factors. As neurons are not continuously active in vivo, the latter mechanism is likely to be important for activity-dependent pro-survival signals to have sustained effects during electrically quiet periods.The project aim is to define which activity-dependent changes in gene expression are responsible for promoting the long-lasting phase of activity-dependent neuroprotection.Specifically:1.Toinvestigate the cellular events underlying neuronal apoptosis which are prevented by an episode of synaptic NMDAR activity2.To use gene microarray expression analysis and bioinformatics to identify candidate CRE-regulated pro-survival genes that are induced by synaptic NMDAR activity.3.To ascertain the role of candidate CRE-regulated genes in synaptic NMDAR-dependent neuroprotection by knock-down and over-expression studies.4.To characterise the transcriptional regulation of the identified neuroprotective genes.

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Grant Details

Amount Awarded 265087
Applicant Surname Hardingham
Approval Committee Molecular and Cellular Neuroscience Funding Committee
Award Date 2005-10-20T00:00:00+00:00
Financial Year 2005/06
Grant Programme: Title Project Grant
Internal ID 078178/Z/05/Z
Lead Applicant Prof Giles Hardingham
Partnership Value 265087
Planned Dates: End Date 2009-12-31T00:00:00+00:00
Planned Dates: Start Date 2006-03-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Scotland