Objective
G protein-coupled receptors (GPCR) mediate the action of messengers, which are key modulators of the function, growth and differentiation of cardiac and vascular cells. Alpha and beta adrenergic, angiotensin or endothelin receptors are major targets of pharmaceutical compounds very frequently used in the management of chronic heart failure, angina pectoris or hypertension, which are leading health problems in the European Union. G protein-coupled receptor kinases (GRKs) and arrest in proteins are critical components of the regulatory network which modulates the function of GPCR and triggers receptor desensitisation (=loss of function) upon agonist stimulation. Such important role suggest that changes in the expression or function of GRKs and arrestins may affect the efficacy of signal transduction systems and underlie pathophysiological processes. In fact, marked desensitisation of Beta-adrenergic receptors is a major mechanism in congestive heart failure, and an increased expression of the GRK2 isoform in the failing human heart has been recently reported by partners of this proposal, thus suggesting a potential role for alterations in these regulatory proteins as primary or early events in the development of heart failure.
Other recent data obtained in transgenic models also suggest an essential role for this protein in regulating cardiac cell function, growth and differentiation. Alterations in GRKs and arrestins may also affect the function of GPCR systems other than Beta-adrenergic which are related to cardiovascular pathophysiology, as alpha1-adrenergic receptors or angiotensin II AT1 receptors, which mediate processes of cardiac and vascular hypertrophyand remodelling.
In this context, the aim of this proposal is to elucidate the physiological and pathophysiological roles of GRKs and arrestins in cardiovascular function and disease and their molecular mechanisms of function, by putting together the experience and experimental tools of leading European groups in the field of GPCR regulation mechanisms.
The main specific objectives are the following:
- To investigate the expression and function of different GRKs and arrestins during the development of heart failure;
- To identify the signals and mechanisms governing the expression and function of these proteins in different cell types of the cardiovascular system;
- To study the role of selected GRKs, arrestins and GPCR in cardiovascular physiology and disease, by generating and characterizing transgenic animals in which the content of these proteins (or of receptors involved in cardiac function and hypertrophy such as alpha-adrenergic) has been altered by genetic manipulation and cross-breeding between modified animals;
- To perform a genetic analysis of the potential association between modifications in the GRK2 and +arrestin-1 genes and the occurrence of cardiovascular disease.
Such studies are expected to provide relevant information for the identification of new drug targets and the development of alternative therapeutical strategies for the management of cardiovascular diseases.
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 basic medicine physiology pathophysiology
- medical and health sciences medical biotechnology genetic engineering
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences clinical medicine cardiology cardiovascular diseases
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Coordinator
28049 CANTO-BLANCO - MADRID
Spain
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