Objective
The IL-1 system plays a central role in a variety of inflammatory, infectious and neoplastic conditions and represents a prime target for the development of novel therapeutic and diagnostic agents. The general objective of the present study is to define novel molecular tools and targets within the IL-1 system which may lead to innovative approaches to diagnosis and therapy. The applicants have contributed to the identification, measurement and characterization of molecules and functions in the IL-1 and related fields and will act synergistically. The presence of complementary industrial (SME) partners will ensure immediate transfer of the results obtained to application (see Fig.l). Work will develop along the following connected lines.
1. Receptors. The applicants have identified the type II receptor (R) as a decoy molecule regulated following exposure to prototypic pro- and anti-inflammatory molecules and present in biological fluids. The function of the decoy R and the regulation of its release will be further explored using truncated molecules and gene transfer approaches. Bifunctional inhibitors capable of blocking IL-1 as well as other inflammatory cytokines (e.g. TNF) will be constructed and their potential explored. The molecular and functional properties of a new form of the signal transducing type IR will be explored.
2. Signal transduction. The signal transduction pathway used by IL-1, as yet poorly understood, will be explored. The possibility that IL-1 may act intracellular by will be analysed. Analysis will take advantage of the cellular and molecular systems in 1, 3 and 4. The signal transducing capacity of a new isoform of the type I receptor will be investigated.
3. IL-1 responsive elements and inducible genes. Analysis of a recently identified IL-1 responsive element and factor will be pursued with cloning of IL-1 NF. Its role in the induction of a novel gene, PTX3, recently cloned in endothelial cells and representative of a new gene family will be studied. The biology and role in pathology of PTX3 will be explored, using novel reagents (see 6).
4. The IL-1 and IL-1 receptor antagonist (IL-lra) gene. Studies on the genomic structure and control elements of IL-1 and IL-1ra will be pursued. The possibility that gene polymorphisms may provide markers for disease susceptibility will be explored. A new IL-1ra was recently identified. This molecule will be studied in relation to the genomic organization of classic IL-1ra (see 3).
5. Design of new inhibitors. The definition of molecules, receptors, transduction pathways and gene control elements will provide molecularly defined targets for drug design and testing. Specifically, the following therapeutically oriented lines will be explored: a. evaluation of the potential in models of pathology of the new recently cloned IL-1ra and the possibility that it may affect other components of the system (e.g. IL-1 converting-enzyme); b. the design of novel inhibitors along pathways used by members of this group for other inflammatory agents; c. the design of bifunctional inhibitors (see 1).
6. Role in Dathology. A prime objective of this application is to develop new reagents to identify and measure the various components of the IL-1 system in tissues and body fluids. Development of reliable tools (probes, antibodies, immunoassays) will allow a comprehensive assessment of the function of the system in pathology, and thus provide diagnostic instruments to guide and monitor therapeutic efforts.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences medical biotechnology genetic engineering gene therapy
- medical and health sciences basic medicine medicinal chemistry
- medical and health sciences basic medicine pathology
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Coordinator
20157 Milano
Italy
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