Grant: Project Grant

Human autosomal dominant polycystic kidney disease (ADPKD) is the most frequent hereditary disorder, afflicting 1 in 500 individuals. ADPKD is a severe condition with major impact on health and accounts for ~10% of all cases of end stage renal disease in Canada and worldwide. It is characterized by development of multiple renal cysts that can be detected in childhood, and grow in number and size over time, completely destroying the kidneys. Other organs are also frequently affected like liver, brain, and heart. Presently, progression of ADPKD is unstoppable: kidneys become non-functional and patients die if they have no access to hemodialysis or kidney transplant. A therapeutic strategy for ADPKD that could prevent or even delay renal destruction by a factor of 2- to 3-fold, would minimize cystic disease, improve quality of life and prolong very significantly lifespan. This research project aims at understanding the cellular and molecular mechanism(s) that lead to ADPKD. The PKD1 gene is responsible for ~85% of ADPKD cases. We study the molecular pathology associated with defective PKD1 gene in the mouse, the best experimental system. Our laboratory developed novel genetically modified Pkd1 mouse models that reproduce typical kidney symptoms of ADPKD. We will investigate the mechanism(s) of cyst formation and expansion with Pkd1 models. Cyst expansion is governed by proliferation and fluid secretion under the control of ion-fluid channels as KCNN4. We will test whether KCNN4 is the major channel responsible for cyst expansion by complementary genetic and pharmacologic approaches. We will also dissect the cellular and molecular mechanisms of KCNN4 in ADPKD pathology. Significantly, a KCNN4 specific inhibitor has been developed and tested in sickle cell disease clinical trials. We hope to repurpose this drug for ADPKD and delay renal destruction as prevention if not cure, and even be valuable to target at large, other renal cystic diseases.