Molecular mechanisms of GPCR heteromers signaling
This project aims to elucidate the molecular mechanisms of GPCR heteromer assembly and signaling, focusing on the mGlu2-5HT2A complex to advance drug development for schizophrenia.
Projectdetails
Introduction
G Protein Coupled Receptors (GPCRs) are key mediators of how cells sense and react to their outside environment. Traditionally, these receptors have been thought to function as individual units at the cell surface. Over the past decade, new evidence has shown they can assemble in larger complexes to form new signaling entities and vastly expand a cell’s capacity to respond to its environment.
Importance of Heteromers
Thanks to their strong tissue-specificity, these complexes - termed heteromers - also form important targets for the development of new drugs with fewer side effects. Still, our understanding of the molecular mechanisms by which the assembly of GPCRs in complexes transforms their signaling properties remains extremely sparse.
Research Focus
My proposal investigates how heteromers interact and integrate changes in their environments to generate unique cellular responses. I focus my research on the mGlu2-5HT2A heteromer, as its existence has been demonstrated in humans and is involved in schizophrenia, a debilitating condition that urgently requires new treatments.
Objectives
This proposal is organized into three objectives:
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A too often overlooked component of a GPCR environment is the lipidic membrane it is inserted in. Using a multi-scale biophysics approach, I will characterize the essential role lipids play in the assembly and function of heteromers, but also how receptors themselves change the membrane they are inserted in to transmit information.
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I will use cryo-electron microscopy to solve the first structure of a heteromer, bound to its signaling partners, G proteins. I will go even further and develop cutting-edge EM tools to resolve a high-resolution movie of a GPCR heteromer signaling cascade, from receptor assembly to G protein activation.
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Finally, using single particle cryoEM and fluorescence, I will investigate how heteromers recruit other partners which in turn modify receptors to form these new signaling units.
Financiële details & Tijdlijn
Financiële details
Subsidiebedrag | € 1.499.494 |
Totale projectbegroting | € 1.499.494 |
Tijdlijn
Startdatum | 1-2-2024 |
Einddatum | 31-3-2029 |
Subsidiejaar | 2024 |
Partners & Locaties
Projectpartners
- CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRSpenvoerder
Land(en)
Vergelijkbare projecten binnen European Research Council
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Decoding the Molecular Logic of GPCR Signaling
SignAlloMod aims to decode GPCR signaling logic at the single-molecule level using a novel method to enhance drug discovery and pharmacological interventions.
Unravelling the Physiological Roles of GPCR Voltage Dependence
This project aims to investigate the physiological roles of GPCR voltage dependence in Drosophila using electrophysiology and imaging to understand its impact on neuronal activity and behavior.
Unravelling Signalling Heterogeneity using DEEP Learning and MECHANIstic Modelling
This project aims to develop innovative computational methods combining deep learning and mechanistic modeling to predict cell signaling responses and address heterogeneity in cancer treatment.
Synthetic and structural biology of Rab GTPase networks
This project aims to elucidate the self-organizing mechanisms of Rab GTPase networks using synthetic biology, cryo-electron microscopy, and microfabrication to enhance understanding of eukaryotic cell organization.
Mechanisms of co-translational assembly of multi-protein complexes
This project aims to uncover the mechanisms of co-translational protein complex assembly using advanced techniques to enhance understanding of protein biogenesis and its implications for health and disease.
Vergelijkbare projecten uit andere regelingen
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Universal GPCR Activity Sensor for Next Generation Drug DiscoveryThis project aims to develop a novel single-assay technology platform for GPCR drug discovery, enhancing detection and classification of drug candidates to improve efficacy and reduce failures. | EIC Pathfinder | € 2.965.384 | 2023 | Details |
Universal GPCR Activity Sensor for Next Generation Drug Discovery
This project aims to develop a novel single-assay technology platform for GPCR drug discovery, enhancing detection and classification of drug candidates to improve efficacy and reduce failures.