DC 3: New Elements of Nutrient Signal Integration by the TSC complex

Project part of Work Package 1

Objectives: Using high resolution mass spectrometry (HR-MS) combined with CRISPR, knockdown, small compound inhibitors and/or PROTAC degrader techniques, the PhD candidate will discover and characterize new elements mediating the integration of nutrient signals by the TSC complex. Mathematical model-based computational simulations will enable the systematic generation and ranking of hypotheses on the mechanisms via which the candidates act on TSC-mTORC1 signaling. Metabolic effectors will be identified by MS-based metabolomics. In collaboration with the MENTOR partners, we will delineate the role of novel TSC complex regulators in pathophysiological processes linked with mTORopathies.

Expected Results: DC3 will identify and characterize:

nutrient signals to the TSC complex
metabolic outcomes
related targetable mechanisms for diagnostics and treatment of mTORopathies

Prospects of career development: The alumni from the Thedieck lab have successfully transitioned to new positions in both academia and industry. We support multidisciplinary training and advocate for active teamwork in science, providing opportunity for individual development of interests and career paths.

Planned secondments: 2 months at the University of Tübingen for generation of PROTAC degraders of new amino acid responsive TSC regulators. 2 months at FORTH-BRI for identification of translation targets downstream of new TSC regulators. 3 months at PD-value for linkage of ODE based computational mTOR models with pharmacokinetic models to account for drug metabolization.