Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic disease with variable expression that is characterized by cyst formation in ductal organs, principally the kidneys and liver, vascular aneurysms, cardiac valve defects and colonic diverticulae. Genetic studies have linked the defect to at least three loci, and identified two of the genes os PKD1 and PKD2. Biochemical studies associated cyst formation with abnormal epithelial proliferation, polarity and basement membrane composition, features that characterize, features that characterize the less mature epithelium of developing and regenerating kidneys. Polycystin 1, the product of PKD1, is a developmentally- regulated multi-spanning membrane protein with a large extracellular region consisting of a novel mosaic of protein-protein interaction domains. Polycystin 2, the product of PKD2 is a hexaspanner with cytoplasmic N- and C-termini and homology to a voltage-activated calcium channel. The ADPKD phenotype in patients with mutations in PKD1 or PKD2 differs in disease progression and severity but not in the spectrum of the organs involved. This suggests that the respective proteins, in conjunction with other interacting proteins, function as components of a common pathway of epithelial differentiation in which polycystin 1 serves as a sensor, and regulates a putative ion channel activity of polycystin 2. Our goals are to elucidate the elements of this pathway in order to understand its precise role in terminal epithelial differentiation. We will attempt to define the earliest events (cellular processes and genes) affected by the loss of polycystin 1. We also propose to identify extracellular ligands for polycystin 1, and determine how the interaction of its cytoplasmic regions with 14-3-3 proteins is modulated during differentiation.
These aims will be addressed using basic biochemical, immunochemical, molecular and cell biology techniques and making use of homozygous and heterozygous polycystin 1 knock out mice. The results of these studies should provide important insights into the mechanisms of epithelial morphogenesis during tabular maturation, identify possible modifiers, and suggest potential targets and approaches for therapeutic intervention that may significantly halt the progression of ADPKD.
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