Polycystic kidney disease is the most common inherited disease secondary to mutation of a single gene. Heterozygous germline mutations in the PKD-1 gene and consequent alterations in the amino acid sequence of the encoded polypeptide, polycystin-1, cosegregate with disease in affected cohorts. Somatic mutations in the second allele may be required for onset of or acceleration of cystogenesis. Cystogenesis is associated with and is thought to require dysregulation of growth control and altered matrix structure. These changes are coupled with conversion from an epithelial phenotype of net reabsorption to one of net secretion. However, despite the phenotypic reproduction of aspects of the human disease in PKD1 -/- mice, the discovery of candidate polycystin-1 binding partners, the discovery of alterations in cell signalling produced by overexpression of a polycystin-1 subdomain, the mechanisms by which polycystin-1 mutations lead to a sustained secretory phenotype accompanied by cyst enlargement remain unknown. Overexpression of part of the C-terminal cytoplasmic domain of polycystin-1 as the fusion protein CD16.7-PKD-1(115-226) upregulates cation channel activity in Xenopus oocytes and in HEK293 cells. We hypothesize that perturbation of this or similar functions accompanies the postulated somatic mutation of the normal germline polycystin-1 allele in the occasional tubular epithelial cells of ADPKD-1 heterozygotes that give rise to cysts. We further hypothesize that this dysregulation (or loss of this function) promotes or causes transition from the normal phenotype of net solute reabsorption to that of net secretion typifying cyst epithelial cells in ADPKD. We propose to extend these studies to polarized normal and ADPKD epithelial cells, and to study regulation of this activity. We will search for novel interacting proteins, and prepare protein suitable for structural analysis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK057662-01A2
Application #
6479609
Study Section
General Medicine B Study Section (GMB)
Program Officer
Hirschman, Gladys H
Project Start
2002-05-01
Project End
2006-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
1
Fiscal Year
2002
Total Cost
$284,113
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
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