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Genetic and Chemical Selection of New Molecules which Interfere with Cell Adhesion and Signal Transduction

Objective

- To screen peptide libraries and low molecular weight compounds which interfere with cell adhesion and tyrosine kinase receptors.
- To use DNA delivery systems for inhibition of factors responsible for signalling and restoration cell adhesion.
- To construct mouse lines which will act as drug tester systems.

Cell adhesion is essential for tissue development and organization, and abnormal adhesion plays a key role in a variety of diseases, notably in inflammation, certain diseases of the skin and metastasic cancer. The research is directed toward the discovery of new molecules that interfere with regulation of adhesion and may be used in therapy. It builds on two important development: (i) recent knowledge of the sequences, structures and functional regulation of adhesion molecules and (ii) the discovery that growth factor-induced cell signalling plays a key role in the regulation of adhesion.
We will use three complementary approaches in order to develop cell adhesion therapy. The first will include the screening of (i) peptide libraries for sequences that abolish ligand-receptor binding related to cell adhesion, (ii) phosphopeptide libraries for selection of sequences interfering with receptor-substrate interactions, and (iii) low molecular weight lead compounds for transcriptional activation of the genes for cell adhesion molecules. The second approach will employ DNA delivery systems for inhibition of factors responsible for cell signalling and for restoration of cell adhesion. This will entail the development of DNA delivery vectors with improved cell selectivity and the expression of gene fragments interfering with signalling in a dominant-negative fashion. The third critical approach will involve the construction of mouse lines carrying transgenes for signalling or cell adhesion molecules which will act as drug tester systems.
The proposal combines genetic selection, high-through-put number chemical screening and DNA-based therapy in a single strategy aimed at cell adhesion therapy. Active molecules and specific DNA vectors will be first selected and tested in vitro in sensitive cell receptor assays and subsequently assessed in vivo in mouse transgenic lines.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Stiftung Max-Delbrück-Centrum für Molekulare Medizin
Address
10,Robert-rossle-strasse
13125 Berlin
Germany

Participants (4)

Böhringer Mannheim GmbH
Germany
Address
2,Nonnenwald
82377 Penzberg
INSTITUT CURIE
France
Address
26,Rue D'ulm 26
75248 Paris
The Chancellor, Masters and Scholars of the University of Cambridge
United Kingdom
Address
Cambridge University Medical School
CB2 2QH Cambridge
Università degli Studi di Torino
Italy
Address
Corso Massimo D'azeglio 52
10126 Torino