DC 6: Brain mosaicism affecting the mTOR pathway

Project part of Work Package 1

Objectives: Focal Cortical Dysplasia type II (FCDII) causes severe drug-resistant pediatric epilepsy through mTOR pathway hyperactivation. FCDII-associated epilepsy is typically resistant to anti-seizure medications, and patients ultimately require neurosurgical resection of the epileptogenic zone for seizure control, allowing direct analysis of diseased tissue. The Baulac lab is one of the pioneers in the identification of brain somatic mutations in FCDII affecting various genes belonging to the mTOR pathway and which cause mTOR hyperactivation. However, there are still ~40% of FCDII cases that remain unsolved genetically. Moreover, the cell-type and developmental origin of FCDII abnormal cells remain poorly understood. DC6 will:

discover novel FCDII-causing genes in the mTOR pathway through ultra-deep sequencing;
identify mutation-carrying cell types and their developmental origins using single-cell approaches;
map electrophysiological dysfunction to molecular changes via MEA recordings coupled with spatial transcriptomics from human acute cortical slices and mouse models.

PhD candidate will analyze surgical epileptic brain tissues using cutting-edge genomics (targeted panels, whole exome/genome sequencing, longread sequencing), single-nucleus RNA sequencing, laser-capture microdissection, and integrate functional electrophysiology with spatial transcriptomics.

Expected Results: The PhD candidate will identify the cell types involved in epileptogenesis, determine the developmental origin of abnormal FCDII cells, and elucidate molecular and cellular mechanisms dysregulated by mTOR-activating mutations, while establishing functional correlations between genetic alterations and electrophysiological phenotypes.

Prospects of career development: The multidisciplinary nature of this Research and Educational program provides extensive career opportunities in both Academia and Industry. Previous Baulac lab alumni have achieved successful careers as independent group leaders, tenured researchers, university professors, pharmaceutical industry scientists, and clinical research associates.

Planned secondments: 3 months at FORTH-BRI for brain organoid modeling FCDII gene variants that alter mTORC1 activity. 3 months at Cell Signalling Technology for phospho-specific antibody development of differentially regulated proteins in mutant brains.