Polycystic kidney disease (PKD) is a common genetic disease that is characterized by the development of fluid filled cysts in the kidney and is associated with high morbidity and mortality. Autosomal dominant PKD (ADPKD) affects approximately 1:1000 individuals, whereas autosomal recessive PKD (ARPKD) is seen in approximately 1:20,000 live births. The molecular mechanisms underlying cyst formation remain unclear. The recent work from the Director's laboratory has shown that polycystin-1 and -2 function as a receptor channel complex that mediates G protein and calcium signaling and mechanosensation. The director has developed a number of mouse models with mutations in the mouse ortholog of the human ADPKD gene and generated cell lines from these mouse mutants and their wild type littermates. Taking advantage of these and other reagents developed in the Director's laboratory, the Center investigators will explore the molecular mechanisms underling human polycystic kidney disease. Project 1 (Dr. Denker) will use biochemical, cell biological and genetic approaches to understand the role of heterotrimeric G proteins in PKD. In Project 2 Dr. Kreidberg will use a combination of cell and molecular bioiogical approaches to understand the role of cadherins and integrins in the pathogenesis of polycystic kidney disease. In Project 3 Dr. Zhou will use biochemical and cell biological approaches to understand the role of fibrocystin/polyductin (FPC) in comparison with the roles of polycystins in PKD. Each of these projects will be supported by a Core facility that will provide most up to date support on molecular imaging and an administrative Core. The proposed studies are highly relevant to both the recessive and dominant forms of human polycystic kidney disease. Results from these studies will advance our understanding of the molecular mechanisms underlying cystogenesis and lead to the identification of novel therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Specialized Center (P50)
Project #
5P50DK074030-04
Application #
7494044
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (O1))
Program Officer
Flessner, Michael Francis
Project Start
2005-09-30
Project End
2010-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
4
Fiscal Year
2008
Total Cost
$1,120,506
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Wu, Yong; Xu, Jen X; El-Jouni, Wassim et al. (2016) G?12 is required for renal cystogenesis induced by Pkd1 inactivation. J Cell Sci 129:3675-3684
Yao, Gang; Luo, Chong; Harvey, Michael et al. (2016) Disruption of polycystin-L causes hippocampal and thalamocortical hyperexcitability. Hum Mol Genet 25:448-58
Czarnecki, Peter G; Gabriel, George C; Manning, Danielle K et al. (2015) ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning. Nat Commun 6:6023
Follit, John A; San Agustin, Jovenal T; Jonassen, Julie A et al. (2014) Arf4 is required for Mammalian development but dispensable for ciliary assembly. PLoS Genet 10:e1004170
Yao, Gang; Su, Xuefeng; Nguyen, Vy et al. (2014) Polycystin-1 regulates actin cytoskeleton organization and directional cell migration through a novel PC1-Pacsin 2-N-Wasp complex. Hum Mol Genet 23:2769-79
Wang, Shixuan; Wu, Maoqing; Yao, Gang et al. (2014) The cytoplasmic tail of FPC antagonizes the full-length protein in the regulation of mTOR pathway. PLoS One 9:e95630
Manning, Danielle K; Sergeev, Mikhail; van Heesbeen, Roy G et al. (2013) Loss of the ciliary kinase Nek8 causes left-right asymmetry defects. J Am Soc Nephrol 24:100-12
Yao, Gang; Luyten, Annouck; Takakura, Ayumi et al. (2013) The cytoplasmic protein Pacsin 2 in kidney development and injury repair. Kidney Int 83:426-37
Jonassen, Julie A; SanAgustin, Jovenal; Baker, Stephen P et al. (2012) Disruption of IFT complex A causes cystic kidneys without mitotic spindle misorientation. J Am Soc Nephrol 23:641-51
Qin, Shan; Taglienti, Mary; Cai, Lei et al. (2012) c-Met and NF-ýýB-dependent overexpression of Wnt7a and -7b and Pax2 promotes cystogenesis in polycystic kidney disease. J Am Soc Nephrol 23:1309-18

Showing the most recent 10 out of 34 publications