(Taken directly from the application) Polycystic kidney disease (PKD) is a common genetic condition that results from the swelling of the lumen of the renal tubular epithelia; in addition, other tubular epithelia throughout the body, and in particular the liver, can exhibit similar deformations. The formation and maintenance of tubular diameter are poorly understood processes. Several cloned mammalian genes encode proteins essential for maintaining proper nephritic diameter and preventing cyst formation. Two proteins, termed polycystins, share a region of homology, and are both necessary for normal tubule structure, and prevention of an autosomal dominant PKD. A third protein, Tg737, prevents autosomal recessive PKD in mice. The biochemical functions of the polycystins is unclear; they may function together as an ion channel. Tg737 probably acts to bring proteins together in a complex, although the nature of those proteins is unknown. Close homologues to Polycystin 2 and Tg737 have been found by the genome project recently completed for the relatively simple creature, the nematode Caenorhabditis elegans. This worm is an attractive organism for studying the cellular function through the use of genetic techniques, and to discover the partners of these proteins in determining nephritic diameter. This application proposes: 1) To clone the CePKD-2 and CeTg737 genes from C elegans, and to determine the time and place of expression of these genes and their products during development; 2) To compare the function of the human and nematode PKD2 proteins through the construction of chimeric worm::human PKD-2 genes, and the production and analysis of transgenic nematodes containing these chimeric genes; 3) To create and examine the phenotype of a knockout mutant devoid of CeTg737 function, and to use genetic techniques to discover the proteins with which CeTg737 interacts. These experiments will elucidate the role of polycystin and Tg737 in maintaining tubule diameter, which will provide a major step towards understanding the causes of PKD.
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