Objetivo
Dysfunction of protein Tau is the main cause of dementia. Dementia associates with synaptic failure and sleep disturbances, but their connection remains elusive. In dementia, Tau becomes hyperphosphorylated (p-Tau) causing synaptic loss. Temperature fluctuations also associate with Tau phosphorylation, for example in hibernating animals. Intriguingly, my work demonstrates that brain temperature decreases during sleep, and further evidence suggests there are Tau-sites phosphorylated during sleep. My hypothesis is that sleep (and temperature)-induced Tau phosphorylation drives synaptic plasticity changes during sleep. To investigate this, I will map the dynamic changes in p-Tau during sleep and then delve into the mechanisms by mimicking brain temperature changes that naturally occur during sleep in human-induced neurons and mouse primary neurons. Employing genome engineering, I will interfere with p-Tau during sleep in mice in vivo and evaluate its impact on sleep, sleep-dependent synaptic plasticity and hippocampal long-term potentiation. This research challenges the notion that p-Tau solely drives disease progression, exploring a physiological function for p-Tau in regulating synaptic plasticity during sleep. The result of this project can challenge our understanding of Tau's function and open a new therapeutic avenue: the development of sleep-wake mechanisms to reverse the pathological p-Tau state observed in dementia. With my host lab's prior track record of uncovering critical insights into Tau-induced synaptic dysfunction, it stands as the perfect platform to tackle these questions. Additionally, I find myself in an ideal position, armed with exciting preliminary data that bolsters the validity of this proposal, and a robust technical and scientific background that empowers me to embark on this ambitious research journey. The plan I propose brings us closer to breakthroughs in effective dementia treatments.
Ámbito científico
Palabras clave
Programa(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régimen de financiación
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinador
9052 ZWIJNAARDE - GENT
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