DC 7: How does the mTOR pathway regulate neuronal excitability: towards new therapeutic targets

Project part of Work Package 2

Objectives: Genetic diseases, such as Tuberous Sclerosis Complex (TSC), leading to the up-regulation of mTOR activity predispose to altered cortical development, now classified as mTORopathies, which are associated with epilepsy as well as intellectual disability and autism. However, why aberrant mTOR activity alters neuronal excitability remains unknown. By genetic epistasis experiments in mouse models of the disease, our preliminary data identified one mTOR substrate, S6 kinases 1 (S6K1), as an essential factor for cortical malformations and seizures in a mouse model of TSC. By phospho-proteomics and electrophysiological studies, we observed that S6K1 phosphorylates key determinants of neuronal excitability. We hypothesized that their regulation by S6K1-mediated phosphorylation may contribute to epileptic seizures in Tuberous Sclerosis. The PhD candidate will test this model by original pharmacological, nutritional, biophysical and genetic approaches.

Expected Results: Our project combines expertise in mTOR signaling and animal models of genetic diseases, allowing to explore the contribution of key determinants of neuronal excitability as novel putative therapeutic targets in epilepsy associated with mTORopathies.

Prospects of career development: Over the past 20 years, alumni from the Pende lab became group leaders/tenured researchers in Academia, University teaching professors, Project leaders in Pharma companies, Directors of Technological Facilities, Clinical Research Associates. The job opportunities for the Doctoral Candidates will be expanded by the multidisciplinary nature of the Research and Educational program, leading to potential recruitments in new fields (genetic tests, biomarkers analysis, cellular models, drug discovery and development) in both Academia and Industries.

Planned secondments: 3 months at Mimetas for TSC and TREK1 mutant kidney on a chip. 2 months at Fondazione Telethon (TIGEM) for TFEB/S6K interaction in ependymal cells of TSC mutants. 2 months at IMol for establishing TREK1 mutants in Zebrafish

Other information: Please note that in addition to the selection process conducted by the project consortium, the selected candidate will also be required to participate in a mandatory audition/interview with the doctoral school as part of the formal admission procedure.