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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059599-11
Application #
8490354
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Rasooly, Rebekah S
Project Start
2001-04-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
11
Fiscal Year
2013
Total Cost
$309,399
Indirect Cost
$99,511
Name
University of Oklahoma Health Sciences Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Nesin, Vasyl; Wiley, Graham; Kousi, Maria et al. (2014) Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. Proc Natl Acad Sci U S A 111:4197-202
Ong, E-Ching; Nesin, Vasyl; Long, Courtney L et al. (2013) A TRPC1 protein-dependent pathway regulates osteoclast formation and function. J Biol Chem 288:22219-32
Kim, Sehyun; Zaghloul, Norann A; Bubenshchikova, Ekaterina et al. (2011) Nde1-mediated inhibition of ciliogenesis affects cell cycle re-entry. Nat Cell Biol 13:351-60
Bai, Chang-Xi; Kim, Sehyun; Li, Wei-Ping et al. (2008) Activation of TRPP2 through mDia1-dependent voltage gating. EMBO J 27:1345-56
Feng, Shuang; Okenka, Genevieve M; Bai, Chang-Xi et al. (2008) Identification and functional characterization of an N-terminal oligomerization domain for polycystin-2. J Biol Chem 283:28471-9
Tsiokas, Leonidas; Kim, Sehyun; Ong, E-Ching (2007) Cell biology of polycystin-2. Cell Signal 19:444-53
Li, Wei-Ping; Tsiokas, Leonidas; Sansom, Steven C et al. (2004) Epidermal growth factor activates store-operated Ca2+ channels through an inositol 1,4,5-trisphosphate-independent pathway in human glomerular mesangial cells. J Biol Chem 279:4570-7
Rajala, Raju V S; McClellan, Mark E; Chan, Michael D et al. (2004) Interaction of the retinal insulin receptor beta-subunit with the p85 subunit of phosphoinositide 3-kinase. Biochemistry 43:5637-50
Ma, Rong; Rundle, Dana; Jacks, Jeanie et al. (2003) Inhibitor of myogenic family, a novel suppressor of store-operated currents through an interaction with TRPC1. J Biol Chem 278:52763-72