(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.
| 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 |
