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Spatial and temporal visualization Of Chemokine receptor Desensitization

Final Activity Report Summary - CCR DSENS (Spatial and temporal visualization Of Chemokine receptor Desensitization)

Chemokines and their receptors are central to regulation and housekeeping of the immune system, wound healing, allograft rejection and HIV infection. Their down regulation is essential for maintenance of homeostasis. Dysregulation can lead to pathologies with high levels of prevalence, such as asthma, atherosclerosis and tumour growth, all of which are biomedical priorities in Europe and worldwide. Chemokines are secretory cytokines released in response to endogenous and exogenous stimuli. They activate and direct the migration of leukocytes. They bind to G protein-coupled receptors (GPCR), which constitute the largest family of cell surface receptors in the human genome (approximately 800 members).

G protein signalling is the target of 30 % of drugs currently on the market, and is the most prominent target for future drug development programs in pharmaceutical research. By a proteomic approach, we identified proteins that are essential to signalling by the CCR2 chemokine receptor.

Our studies provided new insights into the molecular mechanisms of how desensitisation, re-sensitisation and signalling occur. They also revealed unsuspected specificity and plasticity in the signalling regulation of GPCR by endocytic membrane trafficking. They suggest new mechanisms that could be exploited to define putative targets for therapeutic intervention in high prevalence pathologies including atherosclerosis and asthma which are burden for the health care systems of many nations.