Objective OBJECTIVES: the dynamic process of neural development essentially depends on the co-ordinated performance of cellular adhesion events. Among the best characterised molecules involved in the regulation of these processes is the neural cell adhesion molecule, NCAM. A remarkable feature of NCAM is its ability to carry an unusual posttranslational modification, the polysialic acid (PSA). PSA expression correlates with stages of cellular motility and recent data implicate its function in synaptic plasticity and in tumor malignancy. The first molecular cloning of PST-1 in the coordinator's laboratory is a pioneering step in evaluating the biological function of PSA. The large number of neurobiological studies spurred by the availability of PST-1 cDNA and genomic clones exceeds by far the capacity of a single laboratory. Full exploitation of these resources thus requires a co-ordinated, transnational research effort. The studies decribed in this proposal are aimed at enlightening the molecular features of PSA, the biosynthetic pathway and the dynamics of PSA-expression and thus, build the basis for the development of therapeutics suitable to nudge up PSA synthesis (e.g. after nerve injury), or to block PSA-expression at the cellular level (e.g. tumors). Objectives of this proposal therefore are: - Physicochemical studies on the recombinant PST-1 should provide the three dimensional structure of this enzyme, allowing the definition of functionally active sites, and the design of specific PST-1 agonists and antagonists. - Physicochemical data will be confirmed by site directed mutagenesis and analysis of newly generated mutants in a specific in vitro assay system. - Determination of the catalytic mechanism of PST-1 and definition of its acceptor structure further complements the development of agonists and antagonists. - Creation of null-mutants, of mice, which overexpress PST-1, and of mice with cell-type specific conditional expression will help to elucidate PSA functions during development and plastic processes in vivo. Moreover, these animals will provide new model systems to investigate the role of PSA in bacterial meningitis. - Identification of PSA-binding partners and of PSA conformational structure will provide information on the molecular mechanism of PSA-guided processes and on the regulation of PSA-expression. Fields of science natural sciencesbiological sciencescell biologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programme(s) FP4-BIOTECH 2 - Specific research, technological development and demonstration programme in the field of biotechnology, 1994-1998 Topic(s) 0401 - Development of the nervous system Call for proposal Data not available Funding Scheme CSC - Cost-sharing contracts Coordinator Medizinische Hochschule Hannover Address 1,carl-neuberg-strasse 30625 Hannover Germany See on map EU contribution € 0,00 Participants (4) Sort alphabetically Sort by EU Contribution Expand all Collapse all CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE France EU contribution € 0,00 Address 31,campus de luminy 13288 Marseille See on map Eidgenössische Technische Hochschule - ETH Zürich Switzerland EU contribution € 0,00 Address Hönggerberg 8093 Zürich See on map UNIVERSITY OF TURKU Finland EU contribution € 0,00 Address 10,kiinamyllynkantu 10 20520 Turku / abo See on map UTRECHT UNIVERSITY Netherlands EU contribution € 0,00 Address 8,padualaan 8 3584 CH Utrecht See on map
