Towards the Comprehension of Polycystin-1 Function and Identification of Specific Targets for Therapy in ADPKD

Autosomal Dominant Polycystic Kidney Disease (ADPKD) affects approximately one person in a thousand worldwide. This disease causes normally hair-thin tubules in the kidney to balloon into thousands of fluid-filled structures called cysts. The cysts increase in size and number throughout an individual's lifetime causing progression to renal failure. Mutations of two genes called PKD1 and PKD2 cause 85% and 15% of all cases, respectively. In ADPKD patients, the PKD1 and/or PKD2 proteins cannot function properly. Their precise function and the mechanisms causing normal tubules to generate cysts in their absence are still uknown. We propose to use several systems, such as cell cultures and mice models, to understand what is the normal function of the PKD1 gene most commonly mutated. We have developed new models that recapitulate what is most likely the normal function of the PKD1 gene and others that recapitulate what happens in its absence. In addition, we propose to use mice models in which the normal Pkd1 gene has been modified to resemble the disease-associated abnormal gene. We propose to use these models to understand what goes awry in the cystic kidneys when the Pkd1 gene cannot function properly. We believe that understanding the normal function of this gene and how its absence result in cystogenesis is our strongest hope that one day we could "fix" it in ADPKD patients. In line with this, our previous efforts into this direction have allowed us to identify a novel potential therapeutical target for the disease. We propose herein to test if targeting this cascade ameliorates the disease progression in a mouse model recapitulating ADPKD.