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Overall strategy

Central to this project is to unravel and understand the intricate interaction between glial cells and neurons in the formation of a fully functional myelinated nerve and how these signals are disturbed in neuropathy. The participants in this project provide a strong basis to carry out the collaborative project. Collectively these groups represent the cutting edge of European research on glia-neuron interactions in development and disease. Many of the participants have had extensive collaborative connections, both formal and informal over many years. The different and overlapping expertise represented in the consortium will ensure that scientific progress is made. The inclusion of our industrial participant Axxam in the consortium will ensure realistic explorations of potential therapeutic targets identified in the project.

To reach the ambitious goals as defined by the main aim of the project, we propose a workplan structure that combines and covers the relevant disciplines in an integrated fashion. Our proposed collaborative project includes 4 work packages under a common integrated management structure (listed as WP5 and described in detail under section 2.1). In WP1 we will combine the power of fly genetics, mouse genetics and in vitro cultures systems to gain a more detailed understanding of the molecules and mechanisms allowing glial cells to contact, recognize and ensheathe axons. In WP2 we will investigate how axonal signals are transmitted to the glial cell to control myelin formation and how disturbance of these signals results in myelin abnormalities and neuropathy. In WP3 we will determine how glial cells organize the axonal membrane they ensheath. Also in this project we will combine fly genetics and mouse genetics to gain a full understanding of the molecules involved and their mode of action. In WP4 we will test our hypothesis that perturbation of axon-glial interactions are at the heart of the pathogenic mechanism in peripheral neuropathy, perform a pre-clinical trial with Rapamycin to treat structural myelin abnormalities, and we will develop with our industrial participant a cell based assay for high throughput testing of therapeutic molecules. Following the identification of second messengers that stimulate myelination, and encouraging pilot data, we will explore the experimental treatment of a mouse model with hypermyelination resembling human CMT4.

List of Work Packages