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Interference with MEK1 signaling to improve nerve sprouting and regeneration

Reference	BB/D009537/1
Principal Investigator / Supervisor	Professor Gennadij Raivich
Co-Investigators / Co-Supervisors	Professor Patrick Anderson
Institution	University College London
Department	Maternal & Fetal Medicine
Funding type	Research
Value (£)	485,214
Status	Completed
Type	Research Grant
Start date	01/06/2006
End date	28/02/2010
Duration	45 months

Abstract

Changes in intracellular signalling in injured neurons control the ensuing axonal regeneration, sprouting and repair, as well as in posttraumatic cell death, and are regulated by signal transduction enzymes and transcription factors induced after injury. The rapid transcriptional upregulation and phosphorylation of the mitogen-activated protein kinase kinase 1 or MEK1 is an early event in the cell body of axotomized neurons, suggesting that this protein may control the regeneration, sprouting and cell death programs in the injured neurons. Preliminary studies using MEK1 mutants suggest that this enzyme blocks sprouting and enhances inflammation and cell death. Here, novel constructs using neuronal cell type-selective expression of constitutively active or dominant negative forms of MEK1 will now allow us to identify the role of MEK1 in cell death, regeneration and repair in vivo. In addition, pharmacological inhibition and selective inactivation of the downstream targets of MEK1 - ERK1 and ERK2 - will assist in identifying which of the components of the MEK signalling cascade are associated with harmful or beneficial effects. These data are particularly important for identifying new molecular targets essential for developing new pharmacological strategies in treating CNS injury, but they will also be useful in stroke, inflammation and cancer.

Summary

Achieving regeneration in the spinal cord represents one of the major practical challenges in experimental neurobiology. There are two groups of patients with spinal cord damage. Those with incomplete spinal cord transection, show a clear potential for considerable though not complete recovery, through a branching-out process from spared, uninjured fibres. In those, with complete transection, the results are dire, due to the inability of injured fibres to regrow. Interestingly, the current work could help in both groups. The current proposal aims at exploring the effects of a key signal called MEK1, inside the injured nerve cell, on the ability to of these neurons to generate new connections inside brain and spinal cord. It will use genetically manipulated animals that have drastically changed levels of active MEK1 inside the nerve cell. We already know that these animals are more eager to generate nerve connections following damage to peripheral nerves. The key question, to be answered in the current proposal, will be whether this ability could be used to improve recovery following spinal cord damage.

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	Neuroscience and Behaviour, Pharmaceuticals, Regenerative Biology
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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