Objective
Neurons receive multiple signals from other neurons and from glial cells in the form of soluble molecules such as neurotransmitters, neuromodulators, and growth factors. In addition, they are in contact with the extracellular matrix and with the membrane proteins of neighbouring cells. These multiple signals are processed simultaneously and integrated by intracellular signal transduction pathways which are critical during development for the control of neurite extension, synaptogenesis and neuronal growth, and, in the adult, for synaptic plasticity and neuronal survival. We propose to study in neurons a non-receptor protein tyrosine kinase termed focal adhesion kinase (FAK) and the associated tyrosine kineses from the Src family, which are at the crossroads between signalling by neurotransmitters and by the extracellular matrix. Recent work, for a large part carried out independently by the proponents, has shown the presence of FAK in neuronal growth cones and in mature neurons, has identified specific neuronal splice isoforms of this kinase, and has demonstrated its regulation by neurotransmitters glutamate and acetylcholine, and the recently discovered endogenous ligand of cannabinoid CB 1 receptors, anandamide. When it is activated FAK recruits kineses of the Src family (c-Src, n-Src, Fyn) which phosphorylate neighbouring proteins, and trigger well known signalling pathways involving phosphatidylinositol-3-kinase and mitogen-activated protein kinase. Thus, FAK is in a position to regulate directly or indirectly a variety of important aspects of neuronal physiology including neuronal excitability via ion channel phosphorylation, cytoskeletal organization and interactions with the extracellular matrix, gene expression and neuronal survival. Previous work from one of the proponents strongly supports the involvement of FAK in synaptic plasticity. In addition, findings from other laboratories implicate FAK in human diseases including in tumour invasion and metastasis and in the abnormal signalling pathways in Alzheimer's disease.
The discovery of FAK importance in the nervous system is very recent, and its precise function in neurons, as well as many aspects of its mechanisms of regulation have still to be characterized. The objective of this proposal is to bring together the three European laboratories in which most of the present knowledge about FAK in the nervous system has been acquired. By combination of their complementary fields of expertise they will form a European task force which will have the best chances to elucidate the role of the signalling pathways involving FAK in neurons. A joint effort between the three laboratories is required for this goal since the number of techniques and approaches necessary for its implementation is beyond the capacities of any of the isolated partners.
The general objective of this proposal is to determine the role of FAK, and the associated non-receptor tyrosine kineses in neuronal development and synaptic plasticity. The specific aims are:
1) The identification of the specific properties of the neuronal isoforms of FAK
2) The elucidation of the mechanisms by which neurotransmitters and anandamide regulate FAK
3) The production and characterization of mice carrying targeted knock out mutations in neuronal FAK
4) The identification of the dynamic localization and function of FAK during neurite outgrowth and synapse formation.
5) The determination of the role of FAK in long term potentiation and in behavioral models of learning and memory.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- natural sciencesbiological sciencesneurobiology
- medical and health sciencesbasic medicineneurologydementiaalzheimer
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesbasic medicinephysiology
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Call for proposal
Data not availableFunding Scheme
CSC - Cost-sharing contractsCoordinator
75231 Paris
France