COLLECTING DUCT &ASCENDING LIMB-SPECIFIC GENE TARGETING

University Of Utah, Salt Lake City UT

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Abstract

This proposal involves the development of transgenic mice expressing Cre recombinase targeted to the renal collecting duct and the thick ascending limb of Henle's loop. These two nephron segments are of fundamental importance in the regulation of renal electrolyte and water transport and are relevant to human diseases including congestive heart failure, cirrhosis, nephrotic syndrome, hypertension, renal stone formation, urine concentrating and diluting disorders and other kidney diseases. The collecting duct and thick ascending limb are also involved in a variety of developmental disorders, including polycystic kidney disease and medullary sponge kidney. Targeted Cre recombinase transgenic mice will facilitate the development of mice containing cell-specific genetic disruptions of genes thought to be involved in renal development, function or disease conditions. Limiting disruption of candidate genes to specific renal cell types may overcome problems associated with conventional targeting techniques which disrupt genes in all cells of the body that often result in abnormal and even lethal phenotypes. In this research proposal, transgenic mice containing an aquaporin-2 or a uromodulin promoter driving the expression of Cre recombinase will be developed to produce active Cre recombinase in the renal collecting duct and thick ascending limb of Henle's loop, respectively. Multiple founders for each cell type specific target will be developed to assure lines of mice with adequate cell specificity and Cre expression. These animals will be extensively characterized with regard to their ability to cause collecting duct or thick ascending limb-specific gene disruption. Ultimately, the mice will be highly useful in studies directed at evaluating the role of gene products in renal development, function and disease.