Autosomal-dominant polycystic kidney disease (ADPKD) is considered the most common life-threatening, monogenic inherited disease. ADPKD affects over 600,000 people in the US alone and millions worldwide. During disease progression, kidney tubule epithelial cells proliferate to form fluid-filled cysts that eventually replace most of the normal renal tissue resulting in kidney failure in 50% of the patients by age 50. Most ADPKD patients eventually require renal transplantation or life-long dialysis for survival. Mutations in either of two genes, PKD1 and PKD2, are the underlying cause of ADPKD, with PKD1 mutations accounting for over 85% of the cases. The PKD1 gene product, polycystin-1 (PC1) is a large integral membrane protein that interacts with numerous other proteins and regulates several signaling pathways, however the actual purpose of PC1 is poorly understood.
Research in the Weimbs Laboratory has led to numerous seminal discoveries about the mechanisms underlying ADPKD and the function of PC1. This includes the identification of the role of mTOR and STAT signaling pathways in PKD, and the role of signaling mediated by the cleaved C-terminal cytoplasmic tail of PC1.
Current research projects in the Weimbs Laboratory are aimed at investigating molecular mechanisms including the role of PC1 in regulating cellular energy metabolism, and the identification of environmental factors that determine the rate of disease progression in ADPKD. Further research projects are aimed at developing pharmacological compounds, both small molecules and monoclonal antibodies, that specifically target to renal cysts in ADPKD to avoid extra-renal toxicities and allow long-term therapy.