Human chemokines and their receptors: genomic organization of the gene families, functional characterization of their members and relevance to human diseases

Información del proyecto

Identificador del acuerdo de subvención: BMH4982343

Proyecto cerrado

Fecha de inicio 1 Octubre 1998

Fecha de finalización 30 Septiembre 2001

Financiado con arreglo a

• Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Coste total

Sin datos

Aportación de la UE

Sin datos

Coordinado por

UNIVERSITE LIBRE DE BRUXELLES
Belgium

Objetivo

Chemokines are small-secreted proteins that recruit white blood cells to the sites of inflammation. They play a fundamental role in the host defence against infection by viruses, bacteria and parasites. The protective effects of chemokines can however turn harmful to healthy tissues when their expression is inadequate. Chemokines contribute therefore to the damage in a wide range of acute and chronic inflammatory diseases. Chemokines have also been involved in number of other physiological and pathological processes. MCP-1 contributes to the development of artery-blocking plaques in atherosclerosis. Several chemokinare involved in cancer, either as growth factor GRO alpha), or as agents promotineo angiogenesis (IL-8). Others, such as PF-4, have potent angiostatic properties, and are considered as potential anticancer agents. MIP-1alpha, amon others, regulates differentiation, mobilization and proliferation of bone arrow stem cells. Recently, MIP-1alpha, MIP-1beta and RANTES have been identified as the major HIV-suppressive factors produced by CD8+ lymphocytes, and two chemokine receptors (an orphan receptor termed fusin, and CC-CKR5) were shown constitute the accessory factors (in addition to CD4) required for HIV-1 fusion with its host cells. This array of biological functions makes of chemokines and their Gprotein-couple receptors important targets for the pharmaceutical industry, in various therapeutic areas. Importantly, the range of actions of individual chemokines, and the cell distribution of their receptors, is relatively specific, as compared to other cytokine and cytokine receptor families.

Therapeutic agents acting on restricted cell populations can therefore be considered. Nevertheless, much has still to be done to apprehend chemokine signaling as a whole. Over 25 chemokines, and more than a dozen chemokine orputative chemokine receptors have been described, but relatively few links have been made so far between ligands and receptors. This suggests that many remembers, in each gene family, are still to be discovered, an hypothesis largely supported by the results of recent experiments aiming at identifying new molecules. Chemokine and chemokine receptor genes are known to be clustered in the human genome. Taking advantage of this clustering, the aim of the program is to study the ligand and receptor families using an integrated and targeted approach at the genomic level.

The program will specifically:
1) establish precise physical and sequence ready maps of the chemokine and chemokine receptor clusters of the human genome;
2) identify novel members of both families by polymerase chain reaction and shotgun sequencing of BACs;
3) produce recombinant proteins from the newly identified genes, and investigate which chemokines are active on which receptors;
4) determine the cell-type, and/or stimulus-dependent regulation of the genes expression;
5) delineate the array of biological activities of the novel chemokines, by in vitro and in vivo assays; 6)investigate the involvement of novel chemokines and receptors in a variety of human diseases, with a special emphasis on chronic inflammatory diseases and AIDS. Recently discovered chemokines and receptors will be included in this study as well.

This multidisciplinary program will bring together leading laboratories in their respective areas and a European biotechnology company. The expertise of the partners is highly complementary. The research is expected to bring into light new chemokines and receptors that will constitute novel targets for drug discovery. This program and its subsequent developments will therefore contribute to improve the competitiveness of the European biotechnology and pharmaceutical industries.

Ámbito científico (EuroSciVoc)

• ciencias médicas y de la salud › medicina básica › farmacología y farmacia › descubrimiento de fármacos
• ciencias médicas y de la salud › ciencias de la salud › enfermedades inflamatorias
• ciencias médicas y de la salud › medicina clínica › cardiología › enfermedad cardiovascular › arteriosclerosis
• ciencias médicas y de la salud › ciencias de la salud › enfermedad infecciosa › virus de ARN › VIH
• ciencias médicas y de la salud › biotecnología médica › tecnologías celulares › células madre

Programa(s)

• FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Tema(s)

• 5.2 - Analysis of gene function and interaction

Convocatoria de propuestas

Datos no disponibles

Régimen de financiación

CSC - Cost-sharing contracts

Coordinador

UNIVERSITE LIBRE DE BRUXELLES

• Aportación de la UE: Sin datos
• Dirección: 808,Route de Lennik 808 Campus Erasme - Building C ; 1070 BRUXELLES ; Bélgica
• Coste total: Sin datos

Participantes (3)

EUROSCREEN SA

Bélgica

• Aportación de la UE: Sin datos
• Dirección: 7,ROUTE DE LENNIK 802 ; 1070 BRUXELLES
• Coste total: Sin datos

Istituto di Ricerche Farmacologiche 'Mario Negri'

Italia

• Aportación de la UE: Sin datos
• Dirección: Via Eritrea 62 ; 20157 Milano
• Coste total: Sin datos

Katholieke Universiteit Leuven

Bélgica

• Aportación de la UE: Sin datos
• Dirección: 10,Minderbroedersstraat ; 3000 Leuven
• Coste total: Sin datos