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A systems approach to understanding lipid, Ca2+ and MAPK signalling networks

Reference	BBS/E/B/000C0419
Principal Investigator / Supervisor	Professor Len Stephens
Co-Investigators / Co-Supervisors	Dr Nicolas Le Novere
Institution	Babraham Institute
Department	Babraham Institute Department
Funding type	Research
Value (£)	1,314,409
Status	Completed
Type	Institute Project
Start date	01/04/2012
End date	31/03/2017
Duration	59 months

Abstract

Sensing and interpreting external stimulus often involves the recruitment of several cross-regulating signalling pathways. NLN has been studying for many years the biochemical determinant of neuroadaptation. In the chosen model system, the medium-sized spiny neuron of the striatum (existing and planned uplft grant funded work in the lab of MC are focused on this class of neurons giving us significant mass and focus within the ISP), synaptic plasticity and dendritic remodeling, involve several intracellular kinase-dependent signalling pathways acting with different timescales(131). For instance, CaMKII, PI3K and PKC trigger short-term plasticity in seconds through protein modifications and translocation. PKA, ERK (MAPK) and CaMKIV persistently modulate gene regulatory networks and change gene expression. TrkB, a tyrosine kinase receptor for neurotrophins and PI3K/PKB are also involved in long-term effects on for instance dendritic remodelling and neuronal survival. All these kinase pathways are linked through the activation/inhibition of phosphatases, ultimately forming a network of kinases, phosphatases and substrate phosphoproteins with variable dynamics. However, at present the knowledge of these phosphorylation-dependent signalling pathways remains fragmented and largely descriptive. NLN's activity at the BI will follow two lines. (i) He will continue to study the role of Ca2+ signals in synaptic plasticity, developing highly realistic models and benefiting from Llew Roderick’s (Epigenetcis ISPG) expertise in Ca2+ analysis. Those models will help in understanding the respective roles of the proteins constituting the Ca2+-sensitive, long-term potentiation cycle - glutamate ionotropic receptors, calmodulin, neurogranin, calcineurin and CaMKII – in decoding amplitude, frequency and duration of Ca2+ signals. A better grasp Ca2+ homeostasis and dynamics is now acknowledged to be a key to understanding synaptic ageing(132, 133). (ii) NLN's group will use synaptic signalling as a model system to understand the mechanisms and consequences of integrating multiple signalling pathways.

Summary

unavailable

Committee	Not funded via Committee
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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