(Directly taken from the application) Cadherins are Ca++- dependent membrane proteins that are the principal mediators of homotypic cellular recognition and adhesion. Cadherins play a pivotal role in the morphogenic direction of tissue development and maintenance of the terminally differentiated cellular phenotype. ADPKD has been characterized as a morphogenic defect in which the epithelium of affected nephron segments undergoes significant dedifferentiation with concomitant changes in cellular growth rate and alterations in extracellular matrix. We have recently identified a novel, kidney- specific cadherin (Ksp-cadherin) whose epithelial expression appears to be deficient in autosomal dominant polycystic kidney disease. The principal objectives of the proposed study are to define the functional roles played by Ksp-cadherin in the morphogenesis and maintenance of the renal epithelial phenotype, and to evaluate whether deficient expression of Ksp-cadherin causes or promotes renal cyst formation. To accomplish these goals, we will pursue the following specific aims: A. Characterize the expression of Ksp-cadherin in human and mouse kidney: 1) complete the characterization of antibodies to the human isoform of Ksp-cadherin; 2) determine the spatial and temporal patterns of expression of Ksp-cadherin in the human and mouse kidney and correlate with expression patterns of PKDl; and 3) characterize expression of Ksp-cadherin in ADPKD-affected human kidneys and compare with expression pattern of PKDl. B. Determine if altered Ksp-cadherin expression is a common defect in the pathogenesis of renal cyst disease. 1) assess Ksp-cadherin expression in ARPKD, acquired PKD, and simple cysts; and 2) assess the expression of Ksp-cadherin in well-characterized animal models of renal cyst disease such as the cpk/cpk mouse, the pcy/pcy mouse, and the Han:SPRD rat. C. Evaluate the function of Ksp-cadherin in vivo by the targeted disruption of the murine Ksp-cadherin gene: 1) generate Ksp-cadherin deficient (Ksp-/-) mice by targeted disruption of the Ksp-cadherin gene; 2) perform a thorough morphological evaluation of both the developing and adult kidneys of Ksp-/- mice to assess the contribution made by Ksp- cadherin to renal morphogenesis and the maintenance of the renal archetype; 3) assess the impact of Ksp-cadherin deficiency on renal function in both neonate and adult homozygous null mutants; 4) evaluate potential effects of Ksp-cadherin deficiency on the temporal and spatial patterns of expression of murine PKD-l; and 5) cross Ksp-/- mutants with pcy and cpk heterozygous mutants and evaluate potential effects on cystogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DK051045-04
Application #
2770566
Study Section
Special Emphasis Panel (SRC (02))
Project Start
1995-09-30
Project End
2000-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Whyte, D A; Li, C; Thomson, R B et al. (1999) Ksp-cadherin gene promoter. I. Characterization and renal epithelial cell-specific activity. Am J Physiol 277:F587-98