Final Research Grant Report
Olivier Devuyst, MD, PhD, Principal Investigator, and Marine Berquez, PhD, Co-Principal Investigator, University of Zurich, Switzerland
Role of Nutrient Sensing and mTORC1 Signaling in Cystinosis
Cystinosis is a lysosomal storage disease caused by loss-of-function mutations in the CTNS gene coding for the proton-driven transporter cystinosin (CTNS) that exports cystine out of lysosomes. The loss of CTNS results in the lysosomal cystine storage, causing early manifestations of kidney proximal tubule (PT) dysfunction followed by multi-systemic complications and kidney failure.
Lysosomal alterations in cystinosis lead to defective autophagy-mediated clearance of damaged mitochondria, which triggers a signaling cascade driving cell proliferation and apical dedifferentiation, as evidenced by multiple transport defects. However, the mechanisms linking CTNS loss and the resulting cystine storage to imbalances in metabolism and differentiation remain unknown.
In this project, Dr. Devuyst has taken advantage of established disease model organisms and physiologically relevant PT cellular systems in combination with cutting-edge cell biology tools, developed with the support of the CRF, to: (i) investigate whether the loss of CTNS disrupts metabolic homeostasis and differentiation by constitutively activating the mTORC1 signaling at the surface of lysosomes; (ii) dissect how the absence of CTNS and the resulting cystine storage shape the response of mTORC1 signaling in PT cells; (iii) assess the potential effect of targeting mTORC1 pathway by dietary and pharmacological approaches to rescue the lysosome and PT function in cystinosis cells.
Download the final study report.
