Thesis, FRANZEN Rachelle

Abstract

Due to confidentiality constraints, this abstract is intentionally non-exhaustive. Autosomal Dominant Polycystic Kidney Disease (ADPKD), caused by germline mutations in PKD1 or PKD2, is the most prevalent monogenic renal disorder and the fourth leading cause of renal replacement therapy in adults. Loss of polycystin-1 function drives constitutive cAMP overproduction, mTORC1 hyperactivation, and a Warburg-like metabolic reprogramming of cystic epithelial cells. Despite tolvaptan remaining the sole approved disease-modifying therapy, its benefit is modest and restricted because of major polyuria, highlighting the need for strategies exploiting vulnerabilities selectively amplified in the cystic phenotype. Gene Set Enrichment Analysis and O-propargyl-puromycin incorporation assays conducted in the host laboratory identified a significant downregulation of a mitochondria-associated pathway in PKD1-deficient cell lines. Furthermore, a CRISPR-Cas9 screening identified mutliple genes directly or indirectly involved with this pathway. Therefore, the objective of this master's thesis was to test if this pathway is associated with decreased viability in ADPKD and if one of the key target genes from the CRISPR is associated with different molecular signaling.