Our objective is to fully characterise the role played by the transcription factor NFkB in neuronal development, ageing, neuronal function and neurodegeneration.
In particular 6 themes will be explored:
Neurotrophins, glutamate and NFkB
Constitutive NFkB in neurones
NFkB - regulated genes in brain
NFkB in brain development and ageing
NFkB in neuronal excitation, LTP and learning
NFkB in neurodegeneration.
In the first of the themes described in the objectives the ability of neurotrophins and glutamate to activate NFkB in neurones will be further studied. The neurotrophin NGF has recently been shown to activate NFkB via the neurotrophin receptor p75. This may be a key response for nerve regeneration. Glutamate is a key excitatory neurotransmitter which has been implicated in neuronal killing and in long term potentiation. Its effects on NFkB may be important for these events.
Studies on neurotrophins and glutamate will involve receptor analysis, gene induction studies, mechanism of activation and effects in vivo. In the second theme, the role of constitutive NFkB in neurons will be studied. This will involve histological studies, biochemical analysis of NFkB complexes, mechanisms underlying the constitutive activation, determination of responsive genes and the role of NFkB in cerebellar development and function. In the third area, subtractive cloning and differential display techniques will be used on transgenic mice in which NFkB is constitutively active or inactivated to determine which genes in brain are NFkB regulated. The fourth theme will assess the role of NFkB in neuronal development and ageing and will be examined by monitoring NFkB activity in the brains of developing and neonatal mice. Its importance will be assessed in transgenic mice whose neuronal or glial NFkB will either be switched off or constitutively on. These mice will also be used in the fifth area, which will assess the role played by NFkB in neuronal excitation, LTP and learning/memory. Finally the potential involvement of NFkB in neurodegeneration will be studied by assessing the effect of inflammatory cytokines and other neurodegenerative agents on NFkB; analysis of NFkB in a model of focal cerebral ischemia and finally by studying the effects of mating the transgenic mice previously described with transgenic mouse models of neurodegenerative diseases.
Using these strategies it will be possible to fully characterise the NFkB system in brain. It is likely that for some of the processes under investigation the role of NFkB will be pivotal. Overall the work is very likely to point to novel therapeutic targets based on the NFkB system for neurodegenerative disease.
Funding SchemeCSC - Cost-sharing contracts