Polycystic kidney disease comprises a group of genetic disorders caused by mutations in at least 5 genetically distinct genes. The most common form of PKD, autosomal dominant polycystic kidney disease (ADPKD), is one of the most common monogenic genetic diseases (PDPKD) of man, affecting about 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 not only the kidney but also the liver, pancreas, arteries and heart. Polycystins comprise a new class of membrane-spanning proteins. To date, four polycystins, encoded by four genetically distinct genes, have been identified. Polycystins -1, and -2, are mutated in autosomal dominant polycystic kidney disease (ADPKD). Polycystins-REJ and -L, which are mostly closely related to polycystin -1 and -2, respectively, are not yet implicated in disease states. The polycystin family can be divided into polycystin-1 (PC1)-like and polycystin-2(PC2)-like subgroups. Both PC2-like proteins (polycystins-2 and -L) share structural homology with cation channels such as those of the transient receptor potential (TRP) and voltage-gated Ca2+, Na+ and K+ channel families. On the other hand, both PC1-like molecules, polycystins-1 and -REJ, share significant domain and sequence homology to a putative ion channel regulator (receptor for egg jelly) in sea urchins. The object of this renewal proposal is to extend the functional studies of polycystin -1 and polycystin-L. Three main lines of investigation will be pursued. First, further characterization of two previously identified potential binding partners of polycystin-1, and continue to search for polycystin-1 ligands. Second, extending the recent studies that show that polycystin-L has channel properties and determine whether other polycystins (1 and 2) modulate these properties. Lastly, complement these biochemical and biophysical studies with gene targeting experiments to elucidate the biological functions of polycystin-L in vivo.
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