Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited disorders in humans, affecting one in a thousand people in the United States. Patients develop multiple cysts in both kidneys. The cysts progressively result in the destruction of the normal kidney structure and eventually lead to end-stage renal failure in approximately 50% of the patients by the age of 60. There are currently no cures for the disease. ADPKD is caused primarily by mutations of the PKD1 gene, which encodes polycystin-1 (PC1) protein. Therefore understanding of the normal structure and function of PC1 will be critical for the development of effective therapies. We have previously discovered that PC1 is proteolytically cleaved at the G-protein coupled receptor proteolytic site (GPS) in virtually all cell types and tissues in vivo. This reaction, the GPS cleavage, generates a number of previously unrecognized PC1 products. Defective GPS cleavage of PC1 has been found in a subset of ADPKD patients. We hypothesized that GPS cleavage is essential for the complete function of PC1 in the kidney. We have recently demonstrated using a novel mouse model that GPS cleavage of PC1 is essential for proper structure and function of the distal nephron segments in the kidney, but is apparently not required for that of the proximal segments and for embryonic development. We now propose that the cleavage products of PC1 are critically required for the structural integrity of distal segments of the nephron in the kidney. This grant aims at understanding the mechanism by which GPS cleavage regulates the important function of PC1 in the kidney. We propose the studies in three complementary Specific Aims using a combination of biochemical, biophysical, cell-biological methods and animal models.
Specific Aim 1 will analyze structure and function of PC1 products generated by GPS cleavage in an in vitro MDCK model system. This study will likely establish basic principles of GPS functioning.
Specific Aim 2 then looks at the role of the PC1 cleavage products in primary cells and finally in mice.
Specific Aim 3 examines the reason why the proximal segments do not require GPS cleavage. The proposed studies will likely yield important insights into the function of PC1 in normal and disease states of the kidney.

Public Health Relevance

Polycystin-1 is the protein that when defective causes a complicated kidney disease known as autosomal dominant polycystic kidney disease, which at this point has no cure. This study aims to understand Polycystin-1, the reasons it becomes defective, and the ways to prevent it.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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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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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Outeda, Patricia; Menezes, Luis; Hartung, Erum A et al. (2017) A novel model of autosomal recessive polycystic kidney questions the role of the fibrocystin C-terminus in disease mechanism. Kidney Int 92:1130-1144
Cebotaru, Valeriu; Cebotaru, Liudmila; Kim, Hyunho et al. (2014) Polycystin-1 negatively regulates Polycystin-2 expression via the aggresome/autophagosome pathway. J Biol Chem 289:6404-14
Outeda, Patricia; Huso, David L; Fisher, Steven A et al. (2014) Polycystin signaling is required for directed endothelial cell migration and lymphatic development. Cell Rep 7:634-44
Xu, Meixiang; Ma, Liang; Bujalowski, Paul J et al. (2013) Analysis of the REJ Module of Polycystin-1 Using Molecular Modeling and Force-Spectroscopy Techniques. J Biophys 2013:525231
Rowe, Isaline; Chiaravalli, Marco; Mannella, Valeria et al. (2013) Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat Med 19:488-93
Kwon, Michelle; Pavlov, Tengis S; Nozu, Kandai et al. (2012) G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease. Proc Natl Acad Sci U S A 109:21462-7
Schröder, Samantha; Fraternali, Franca; Quan, Xueping et al. (2011) When a module is not a domain: the case of the REJ module and the redefinition of the architecture of polycystin-1. Biochem J 435:651-60
Steigelman, Katherine A; Lelli, Andrea; Wu, Xudong et al. (2011) Polycystin-1 is required for stereocilia structure but not for mechanotransduction in inner ear hair cells. J Neurosci 31:12241-50
Woodward, Owen M; Li, Yun; Yu, Shengqiang et al. (2010) Identification of a polycystin-1 cleavage product, P100, that regulates store operated Ca entry through interactions with STIM1. PLoS One 5:e12305
Li, Yun; Santoso, Netty G; Yu, Shengqiang et al. (2009) Polycystin-1 interacts with inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca2+ signaling with implications for polycystic kidney disease. J Biol Chem 284:36431-41

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