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 Kidney Disease (ADPKD) have been disappointing. DC18 aims at performing a deeper dissection of mTORs upstream regulators and downstream effects, identified in this consortium, involved in cyst progression. For this, we will modulate these players in the mTOR signaling pathway in human renal epithelial cell lines of human patients with ADPKD or contiguous gene syndrome (tuberous sclerosis complex associated with PKD) and analyze their effect on relevant disease-specific cellular phenotypes. In addition, DC18 will expand on the role of altered mTOR as an orchestrator of inflammation during cyst progression. DC18 will investigate the role of the upstream and downstream mTOR associates in human epithelial and immune cells (PBMCs and macrophages) on cytokine production, differentiation, and their interaction (co-cultures). We also hold an extensive longitudinal biobank of biological samples (urine, blood, tissue) of ADPKD and mTORopathy patients and healthy individuals available for the overall benefit of the project.

Expected Results: Evaluate the function of mTOR regulators studied in this project in the disease phenotype in unique human cellular kidney cell lines of ADPKD and TSC patients. In addition to the effects in epithelial cells, we will expand the study toward immune cell function regulation.

Prospects of career development: The multidisciplinary nature of the Research and Educational program and the high level of the research performed at KU Leuven will increase job opportunities leading to potential recruitments in new fields in both Academia and Industries in various disciplines (medicine, biomedical sciences, biology, biochemistry, pharmacology, etc.).

Planned secondments: 2 months at Univrsity Clinic of Essen to investigate the contribution of the candidates to mTORC1 signaling in human patient derived cell lines. 2 months at the University of Fribourg for mass spectrometry-based proteomics approaches. 3 months at Mimetas for patient derived kidney on chip.