Our long-term objective is to understand the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD) as a basis for therapy. Autosomal dominant polycystic kidney disease (ADPKD) is the most common lethal monogenic genetic diseases of man, affecting approximately 1 in 1,000 individuals. ADPKD leads to cystic replacement of renal tissue and progressive renal failure, requiring renal replacement therapy in half of the cases by age 50. It is a systemic disease involving the kidney, liver, pancreas, arteries, and the heart. Mutations in PKD1 and PKD2 cause almost all cases of ADPKD. PKD1 and PKD2 encode polycystin-1 and -2 (PC1 and PC2), respectively. Others and we have recently shown that PC1 acts as a G-protein coupled receptor, and PC2 functions as a Ca2+-permeable cation channel, which suggest important roles of polycystins in G protein and Ca2+ signaling. PC1 and PC2 seem to play critical roles in embryogenesis as genetically engineered mice lacking either protein are embryonically or perinatally lethal with severe kidney and pancreatic cyst disease. The first funding period was used to isolate the mouse Pkd2 and PKD2-1ike cDNAs; to determine the channel activity of PC2 and polycystin-L, a PC2-like molecule; to develop antibodies to PC2 and PCL; and to generate a conventional Pkd2 knockout mouse. The major object of this renewal proposal is to continue our studies on PC2 to understand the signaling pathways mediated by polycystins and the molecular mechanism leading to cyst formation. We will focus on four lines of investigation: 1) we will identify the downstream signaling pathways of PC2 using the yeast two-hybrid system; 2) we will generate a tissue-specific knockout mouse line by disruption of the pore region of PC2; 3) we will derive kidney epithelial cell lines from Pkd2 mutants and their wild type littermates; 4) we will study the effect of PC2 mutation on Ca2+ and G-protein signaling. In the longer term these studies will lead to the development of therapies that might palliate or cure ADPKD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053357-07
Application #
6706412
Study Section
Pathology A Study Section (PTHA)
Program Officer
Rasooly, Rebekah S
Project Start
1998-02-21
Project End
2007-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
7
Fiscal Year
2004
Total Cost
$366,956
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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