Projektbeschreibung
Die Architektur synaptischer Proteine in Gesundheit und Krankheit
Die Übertragung neuronaler Information erfolgt im Gehirn über spezialisierte Strukturen, die als Synapsen bezeichnet werden. Sie enthalten über 2 000 unterschiedliche Proteine, doch ihre räumliche Organisation, ihre Architektur und ihr Interaktionsnetz konnten bisher nicht umfassend dargestellt werden. Forschende aus der EU-finanzierten Initiative SynLink wollen eine vernetzende Massenspektrometrie-Pipeline für die Strukturanalyse des synaptischen Proteoms entwickeln. Der SynLink-Ansatz wird dazu beitragen, die Umstrukturierungen und Veränderungen im Synapsennetzwerk zu finden, die bei Lernvorgängen und Gedächtnisbildung ablaufen. Vor allem kann der Ansatz genutzt werden, um synaptische Fehlfunktionen zu untersuchen, die bei mehreren neurologischen und psychiatrischen Erkrankungen auftreten.
Ziel
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.
Wissenschaftliches Gebiet
- natural sciencesbiological sciencesneurobiology
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- medical and health sciencesclinical medicinepsychiatry
- natural sciencesphysical sciencesopticsmicroscopysuper resolution microscopy
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-STG - Starting GrantGastgebende Einrichtung
12489 Berlin
Deutschland