CCR DSENS · Spatial and temporal visualization Of Chemokine receptor Desensitization
6РП — Действия „Мария Кюри“
- Период
- 2006-01-01 → 2007-12-31
- Финансиране от ЕС
- 80 000 €
- Участници
- 1
- Схема
- IRG
Линиите свързват координатора с партньорите.
Накратко на български
Хемокинният рецептор CCR2 и начинът, по който той се активира и изключва, се анализират чрез протеини и мембранен транспорт. Разбирането на тези механизми помага при търсенето на нови цели за терапия срещу астма и атеросклероза.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
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.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
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.
Оригинален текст от CORDIS (на английски).
Участници
- CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS · MADRIDКоординаторИспания
Връзки
Данни: CORDIS, © Европейски съюз