Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common Mendelian disorders in humans affecting 1/1000 worldwide. The hallmark of the disease is the development of multiple cysts from renal tubules in both kidneys, resulting in end-stage renal failure in 50% of the patients. ADPKD is a systemic disease with many ex-renal manifestations. Since the PKD1 gene was identified in 1995, significant efforts have been made in understanding of the biology underlying the disease. But the normal function its gene product, polycystin-1, is still poorly understood. The question of how a mutation in the single PKD1 gene leads to a vast array of defects is also unresolved. The long-term goal of our research is to understand the normal biological function of polycystin-1 during the development and its role in the maintenance of adult organs, and the mechanisms by which PKD1 mutations cause the disease. Post-translational modifications of the protein are known to play a critical role for its activity and such processes have been implicated for the function of polycystin-1. We have found that polycystin-1 undergoes proteolyctic cleavage in vivo. Our preliminary results have indicated that this type of the post-translational processes is likely important for the functionality of polycystin-1. In the grant application, we propose to investigate the role of the proteolytic cleavage of polycystin-1 using a combination of chemical, biochemical, genetic and cell biological approaches. We plan to examine the functional significance of this process in the cell culture system and in the mouse. Furthermore, we propose to characterize the mechanism of regulation of the cleavage reaction and analyze the cellular machinery of the process. This scientific query will likely provide important insights into the functions and novel mechanism of the regulation of potycystin-1. Our investigation will also likely provide clues of the mechanisms by which PKD1 mutations cause the disease. The information from our studies will likely open new avenues in the research of ADPKD and establish the foundation for developing causative and effective therapies of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062199-02
Application #
6726132
Study Section
General Medicine B Study Section (GMB)
Program Officer
Rasooly, Rebekah S
Project Start
2003-04-01
Project End
2008-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
2
Fiscal Year
2004
Total Cost
$315,454
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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

Showing the most recent 10 out of 17 publications