Research Project
2152180
We have identified a new insertional mutation in the mouse that develops a form of polycystic kidney disease with a liver and kidney pathology that closely resembles that in human patients with autosomal recessive polycystic kidney disease (ARPKD). We have cloned the mutant locus and have identified a gene, Tg737 whose expression is directly associated with the mutation in this line. Most important, we previously demonstrated that the Tg737 is directly associated with the kidney phenotype in this mutant line by "rescuing" the cystic kidney trait in homozygous animals utilizing a full-length cDNA of the gene. Since the latter result provides an unequivocal connection between the Tg737 gene and renal cystic disease, in this proposal we plan to further explore the role of the Tg737 gene in normal kidney function and in the development of renal cysts. Specifically we will analyze the temporal/spatial expression of the Tg737 mRNA and protein to determine where within the developing and adult kidney the Tg737 gene is expressed. We will also generate an inducible transgenic line with the Tg737 cDNA in an attempt to better understand when the expression of the gene is most critical to prevent cyst formation. With the inducible transgenic line, we are particularly interested in determining whether induced expression of the Tg737 cDNA after cysts begin to form can lead to a regression of the cystic structures. Additionally, and most important, we plan to use a combination of procedures to begin to characterize other genes whose expression may be altered in the mutant kidneys as a consequence of inactivating the Tg737 gene. We will specifically be interested in studying the role of the epidermal growth factor receptor (EGFR) in the formation and progression of cysts since, in our mutant line, we have determined that the EGFR is over-expressed and mistargeted to the apical surface of the epithelial cells lining the renal cysts.
