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Molecular genetics and pathology of signal transduction

Research project P4/30 (Research action P4)

Persons :

Description :

For the unicellular organism, the aptitude to probe its environment and to react appropriately is fundamental to survival and mating. In metazoans, the same is true for the individual; moreover, for a given cell type or tissue, the aptitude to sense biological signals from other cells within the internal milieu is central to ontogeny and to virtually every physiological process. The wide conservation of signal transduction mechanisms makes it fruitful to put together in a common research program several groups that are studying evolutionary distant model systems within a common conceptual framework.

The aim of the project is to pool the expertise of nine Belgian laboratories to explore the "hardware" and "software" of biological signal transduction at three main levels:

1. the cell surface, where many biological signals are first decoded by interaction with membrane receptors;
2. the nucleus, where gene expression is controlled by transcription factors, some of which are themselves receptors while others are either controlled by regulatory cascades initiated at membrane level or depend on the differentiation events;
3. the biochemical regulatory mechanisms and enzymatic activities that link membrane receptors to nuclear or cytoplasmic effector targets.

The following points will be studied in depth:

1. Membrane receptors:
- characterization of new subtypes of G-protein-coupled receptors (GPCRs) recognising known ligands;
- cloning and characterization of new GPCRs whose ligands are unknown (orphan receptors), with special emphasis on chemokine and neuropeptide receptors;
- identification and isolation of new endogenous ligands corresponding to orphan receptors in insects and mammals;
- study of the function of new ligand-receptor couples by gene disruption (homologous recombination);
- study of structure-function relationships of GPCRs;

Regulation of gene expression:
- construction of libraries of cDNAs or genes coding for nuclear proteins as a source of new transcription factors;
- study of the mechanisms and characterization of factors involved in transcriptional regulation by cAMP, Ca2+, androgens, glucocorticoids, deltanoids, retinoids, thyroid hormones, insulin, glucose and growth factors;
- identification and cloning of genes involved in the regulation of growth and differentiation by cAMP, androgens, and deltanoids;

Intracellular signalling cascades:
- study of differences and interactions between cAMP-dependent and growth-factor-dependent mitogenic pathways;
- study of glucose-dependent mechanisms controlling regulatory cascades; identification and comparison of glucose-dependent control mechanisms in higher eukaryotes and yeast.

In each of the above studies, the relations with disease-causing mechanisms will be investigated. The project can be expected to produce new pathophysiological information in the fields of oncogenesis and tumor invasion, hyper(hypo)thyroidism, neuropathology, diabetes, infertility and inflammation.

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