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The role of the neural cell adhesion molecule L1 and its ligands in normal brain development and hereditary brain diseases

Objective



During development of the nervous system, axonal growth, neuronal migration and synapse formation are essential. As the embryonic nervous system differentiates, neurons produce axons that travel through diverse and changing environments of the developing animal to find their appropriate targets. When target cells are reached, synapses are formed. Synaptic plasticity is important, not only during establishment of the neural network, but also in the adult organism in which a continuous modulation of synaptic connections is essential for the dynamic functions of the brain such as learning and memory storage. An understanding of the molecular basis of axonal growth and guidance both during normal development and in relation to brain diseases is therefore an important issue in developmental neurobiology as well as in clinical neurology and neuropathology.
The aims of the proposed collaboration are to provide an extensive characterization of a key molecule, the neural cell adhesion molecule L1, involved in axonal growth, neuronal migration and synaptic plasticity. The characterization includes localization of binding sites for the homophilic (L1) and heterophilic ligands the cell adhesion molecules Axonin- 1, F11, NCAM and laminin. Furthermore, L1 interaction with the fibroblast growth factor receptor, which probably mediates signal transduction, will be characterised in detail. The binding sites will be characterised in regard to their localization, structure and binding affinities, thus enabling the preparation of agonistic and antagonistic ligands, which may allow the development of compounds beneficial for the treatment of neuro-degenerative disorders. The proposed collaboration involves seven leading European laboratories, six academic and one industrial laboratory. The partners will combine different fields, disciplines and techniques in order to exploit complementary approaches in an integrated manner allowing the achievement of results, which cannot otherwise be obtained. The collaboration will also contain a training element in molecular biological and pharmacological methodology, and it is intended to develop theoretical and practical insights and strategies by means of a progressive series of intensive workshops. By the conclusion of the project, we expect to have identified the major macromolecular ligands of L1, and to have determined their binding sites, binding affinities and effects. Ligands, fragments of ligands and artificial ligands will have been prepared and tested for agonistic and antagonistic effects in-vitro and in-vivo. Finally, these findings will be disseminated by specialist, review and popular articles and conference presentations, providing a platform for future pharmacological developments in the fields of neurodegenerative disorders.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

UNIVERSITY OF COPENHAGEN
Address
3,Blegdamsvej 3C
2200 Koepenhagen
Denmark

Participants (6)

CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS
Spain
Address
Universidad Autonoma De Madrid, Cantoblanco
28049 Madrid
H. Lundbeck A/S
Denmark
Address
9,Ottiliavej 9
2500 Valby
MAX DELBRUCK CENTER FOR MOLECULAR MEDICINE
Germany
Address
10,Robert-rössle-straße 10
13122 Berlin
THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
United Kingdom
Address
Hills Road Addenbrooke's Nhs Trust 5
CB2 2QQ Cambridge
United Medical and Dental Schools of Guy's and St Thomas's Hospitals
United Kingdom
Address
London Bridge
SE1 9RT London
Universität Zürich
Switzerland
Address
190,Winterhurerstraße
8057 Zürich