Many biologically active molecules signal via membrane-bound receptors coupled to heterotrimeric G proteins, and are therefore referred as G protein-coupled receptors (GPCR). They mediate various physiological functions such as vision, taste, calcium, glucose homeostasis and chemotaxis. Chemokines are secretory cytokines able to attract migratory cells. They bind to GPCRs and regulate immune defence, tumour growth, wound healing, allograft rejection, asthma and atherosclerosis. Mechanisms have evolved to fin e-tune and regulate receptor signalling.
Desensitisation consists of inhibiting the response to continuous exposure to the same stimulus; it occurs by uncoupling and inactivation of G protein signalling. The b-arrestins bind to phosphorylated GPCR and physic ally uncouple them from their G proteins, resulting in termination of signalling. Regulators of G protein signalling (RGS) promote desensitisation by accelerating GTP hydrolysis by G proteins, inactivating the signal. Information on how arrestins and RGS act on chemokine receptors and signalling is scarce, and reports are incomplete and/or controversial.
This project aims to study the desensitisation of the chemokine receptors CCR2 and CCR5 in hematopoietic cells using a multidisciplinary approach. We will characterize several receptor-interacting partners using proteomics and determine the temporal and spatial events that occur during CCR signalling and desensitisation by arrestins and RGS19, using total internal reflection microscopy (TIRFM). Using new methods, we will address the questions of how GPCR couple following their heterodimerization, and the functions of RGS in hematopoietic lines.
These studies will provide new insights into the molecular mechanisms of how desensitisation and signalling occur, and will define potential targets for therapeutic intervention. This grant will give me the opportunity to return to the European community of scientists and promote my development as a European experimentalist.
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