ESR6

Investigating the interplay between primary cilia and metabolic rewiring in Polycystic Kidney Disease


The PKD1 and PKD2 genes, encoding for the polycystins, are mutated in Autosomal Dominant Polycystic Kidney Disease. They form a receptor/channel complex in cilia. Cells and kidneys devoid of Polycystin-1 present with metabolic reprogramming and defective mitochondrial structure and function. ESR6 will test the hypothesis that the polycystins enable cilia to sense nutrient availability and to respond by coordinating the metabolic response. Analysis of the cellular response to metabolic stress will be assessed in cilia-less cells (Ift88 or Kif3a mutants), in cells with mal-functioning cilia (Pkd1 and Pkd2 mutants) or in cells carrying subtle ciliary defects (BBSome, the retrograde IFT or the KIF13B/DLG1 complex knock-down in collaboration with P2-UCPH). Cells lacking either Pkd1 or Pkd2 or Ift88 were generated by CRISPR/Cas9. The metabolic response will be evaluated using the SeaHorse, 13C-labelled metabolites tracing (followed by MS) and by morphometrical analysis of mitochondria, lipid droplets and peroxisomes. ESR6 will also identify the mechanism of regulation by testing the role of the GID complex and by exploiting the socioaffinity filtering system in collaboration with partner 1.

Partner: Ospedale San Raffael, Milano, Italy

Supervisor: prof dr A. Boletta