Descrizione del progetto
Scoprire l’architettura delle proteine sinaptiche nella salute e nella malattia
La trasmissione di informazioni neuronali nel cervello avviene tramite apposite strutture note come sinapsi. Le sinapsi contengono più di 2 000 proteine diverse di cui non sono state ancora mappate completamente l’organizzazione spaziale, l’architettura e la rete di interazioni. Gli scienziati dell’iniziativa SynLink, finanziata dall’UE, intendono sviluppare un accesso alla spettrometria di massa cross-linking per l’analisi strutturale del proteoma sinaptico. L’approccio di SynLink contribuirà all’identificazione dei rimodellamenti e delle alterazioni della rete sinaptica che avvengono nei processi di apprendimento e di memoria. È importante notare che tale approccio può essere utilizzato per studiare la disfunzione delle sinapsi, che è alla base di vari disturbi neurologici e psichiatrici.
Obiettivo
Brain function crucially depends on chemical neurotransmission at synapses, while, conversely, synaptic dysfunction underlies neurological and psychiatric disorders. Synapses are composed of more than 2,000 distinct proteins, spatially organized into specialized molecular machineries. During decades of efforts, researchers have acquired a wealth of knowledge on individual key components of the synapse. However, the overall picture of the spatial arrangement, molecular architecture and interaction network of the synaptic proteome remains largely uncharted. Furthermore, innovative methods that allow system-wide profiling of these organizational aspects of synaptic proteins are in great demand.
I propose to develop a highly sensitive cross-linking mass spectrometry (XL-MS) pipeline to analyze structural and organizational features of the synaptic proteome at an unprecedented depth and comprehensiveness. In parallel, I also plan to establish quantitative XL-MS strategies to reveal global network rearrangements and complex-specific alterations during long-term potentiation, which arguably is the most attractive cellular model for learning and memory. Importantly, it is foreseeable that numerous novel insights can be discovered, for which I will use complementary approaches and tools, such as biochemistry, super-resolution imaging, structural modelling and network analysis to validate and interrogate their molecular details and network principles. These studies will yield groundbreaking insights into the molecular architecture of the synapse and thereby fill a crucial knowledge gap in neuroscience. Furthermore, they will provide a framework to gain a deeper understanding of the dynamic regulation in synaptic plasticity and synaptic dysfunction in neurological disorders.
Campo scientifico
- natural sciencesbiological sciencesneurobiology
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- medical and health sciencesclinical medicinepsychiatry
- natural sciencesphysical sciencesopticsmicroscopysuper resolution microscopy
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
12489 Berlin
Germania