Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases. It affects 1 in 1000 Americans with the development of epithelial cysts in the kidney, liver, and pancreas. Naturally occurring mutations in two separate genes, PKD1 and PKD2, are responsible for the vast majority (~99%) of all cases of ADPKD. PKD1 encodes a large plasma membrane protein with a long extracellular domain, while PKD2 encodes an ion channel of the TRP superfamily (currently named, TRPP2). We and others have shown that PKD1 physically interacts with TRPP2 to form an ion channel complex (PKD1/TRPP2) that links extracellular stimuli to Ca2+ influx. However, it still remains unknown how mutations in these genes cause ADPKD. Defects in the limb of the Wnt pathway not associated with beta-catenin (non-canonical Wnt pathway) have been also associated with cystogenesis. We propose that there is a functional interaction between PKD1/TRPP2-mediated signaling and the non-canonical Wnt pathway. We will test this hypothesis by asking: 1) Can pathogenic mutations in PKD1 or PKD2 disrupt non-canonical Wnt signaling pathway? 2) How the activation process of the PKD1/TRPP2 complex is modulated by the non-canonical Wnt pathways? And 3) Do these two pathways intersect in vivo? These questions will be addressed by complementary approaches in cell culture, zebrafish embryos, and the mouse. The proposed studies will help us understand fundamental properties of PKD1 and TRPP2 and their roles in cystogenesis. As the pathophysiological basis of ADPKD is unknown, these experiments will set the stage for the development of therapeutic strategies.

Public Health Relevance

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic diseases. Although the genes responsible for ADPKD have been known for more then thirteen years, no effective treatments are currently available. This is in part due to a gap in our knowledge of how mutations in these genes cause ADPKD. The proposed studies will shed light into this fundamental question.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Cellular and Molecular Biology of the Kidney Study Section (CMBK)
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Rasooly, Rebekah S
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University of Oklahoma Health Sciences Center
Anatomy/Cell Biology
Schools of Medicine
Oklahoma City
United States
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