DC 1: Novel regulators of RAG GTPase mediated Non-Canonical (NC) mTORC1 signaling

Project part of Work Package 1 Objectives : Non-Canonical mTORC1 (NC-mTORC1) signaling controls the function of MiT-TFE transcription factors through substrate recruitment, mediated by RagC/D and Folliculin (FLCN), independently of the TSC-Rheb…

DC 15: S6K1- and S6K2-Selective PROTAC Degraders

Project part of Work Package 3 Objectives: The deconvolution of the individual roles of the mTORC1 downstream kinases S6K1 (RPS6KB1) and S6K2 (RPS6KB2) has mostly relied on genetic tools, and only in the case of S6K1, pharmacological inhibition.…

DC 18: mTOR modulation in kidney mTORopathies: role and effects on epithelial and immunological level

Project part of Work Package 3 Objectives: Despite the well-known contribution of the mammalian target of rapamycin (mTOR) in cyst growth and progression, clinical studies with mTOR inhibitors in the context of Autosomal Dominant Polycystic…

DC 17: Association of metabolic markers and neurological manifestations in patients with mTOR pathway related epilepsy

Project part of Work Package 3 Objectives: The mTOR pathway regulates essential cellular functions, such as protein synthesis, cell growth, and synaptic plasticity, potentially impacting neuronal excitability and epileptogenesis. Genetic…

DC 16: Signaling network modeling of the mTOR and PK-PD modeling of the drug candidates

Project part of Work Package 3 Objectives: DC16 will predict the metabolic stability and blood brain barrier penetration of compounds from existing S6K2 and PI3Kα inhibitor libraries (EKUT-Gehringer and UNIBAS-Wymann). Since most of these…

DC 14: Optimization of S6K2-Selective Inhibitors for In Vivo Application

Project part of Work Package 3 Objectives: The p70 ribosomal protein S6 kinases S6K1 (RPS6KB1) and S6K2 (RPS6KB2) are major downstream effectors of the mTOR complex 1 (mTORC1). While the role of S6K1 is well studied, at least in cancer, knowledge…

DC 13: Establishment of novel covalent inhibitors targeting PI3K/mTOR while minimizing adverse effects

Project part of Work Package 3 Objectives: PI3K and mTOR kinase inhibition are vital strategies for limiting cell growth in mTORopathies and cancer. However, it can lead to mechanism-based adverse effects especially drug-induced insulin resistance,…

DC 12: Cell-autonomous effects of activating RagGTPase mutants in heart and kidney

Project part of Work Package 2 Objectives: Outgrowths, tumors, cysts, renal, cardiac neurological defects and a compromised immune system are present in mTORopathies. Somatic mutations in RagC have been linked to fatal dilated cardiomyopathy,…

DC 11: Shifted metabolism in TSC patients: a new avenue for interventions

Project part of Work Package 2 Objectives: Metabolic differences are promising non-genetic candidate modifiers of the disease course in mTORopathies. Disturbed energy metabolism has been reported in mouse and rat models of TSC, but it is unknown…

DC 10: Kidney on a chip for kidney mTORopathies research

Project part of Work Package 2 Objectives: DC10 will develop a modular, 3D human kidney model in the microfluidic platform OrganoPlate to mimic a kidney architecture and function. In this plate, two channels are separated by a hydrogel. One…

DC 9: General and mRNA-specific translation downstream of mTOR in human neurodevelopment

Project part of Work Package 2 Objectives: One of the best ascribed functions of mTOR is regulation of protein synthesis, also termed translational control. mTOR exerts tight control on gene expression at the level of general translation,…

DC 8: Mechanisms in neuropsychiatric-like behavioral phenotypes and brain connectivity in TSC

Project part of Work Package 2 Objectives: Using zebrafish as an animal model, the PhD candidate will test various compounds and potentially epistatic genes for modification of neuropsychiatric-like behavioral phenotypes in the Tsc2 mutant…

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…

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,…

DC 5: Functional genomics of S6K1/2 specific substrates regulating cell size

Project part of Work Package 1 Objectives: Among the mTORC1 targets, S6 kinases 1 and 2 (S6K1 and S6K2) are exquisitely sensitive to nutrient availability and rapamycin inhibition. Of note, in vivo analysis of mutant mice reveals that S6K1…

DC 4: New approaches to screen for novel direct mTORC1 targets

Project part of Work Package 1 Objectives: Several mTORC1 substrates with functions in anabolic and catabolic processes have been uncovered but their contribution and interplay in mediating mTORC1’s pathophysiological outputs is poorly…

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…

DC 2: Non-canonical Rag GTPase-TORC1 signalling in yeast

Project part of Work Package 1 Objectives: DC2 will address the still elusive mechanism of how the Rag GTPases control TORC1 in yeast. Unlike in mammalian cells where the Rag GTPases serve to tether mTORC1 to lysosomes, yeast Rag GTPases…

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The MENTOR Doctoral Network

Université Paris-Cité (UPCité)
85 Boulevard Saint-Germain,
75006 Paris, France

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Coordinator :

Mario Pende

Project manager :

Magdalena Tortyna

Funded by the European Union under the grant agreement No 101168624. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Executive Agency (REA). Neither the European Union nor the granting authority can be held responsible for them.