A major focus in polycystic kidney disease (PKD) research is to identify genes involved in renal cyst development. Despite recent successes in cloning several human PKD genes, their roles in disease pathogenesis remain undefined. In addition, it appears that genetic background influences the expression of many PKD disease-susceptibility genes. The characterization of these putative modifying genes will be quite difficult in the complex, randomly mating, human population. As an alternative, mouse PKD mutations and their genetic modifiers may provide powerful resources to study genes and gene interactions involved in renal cystogenesis. Among the several mouse models in which PKD segregates as a single Mendelian trait, three mutations, cpk, bpk, and Tg737Rpw, closely resemble human autosomal recessive polycystic kidney disease (ARPKD). In these three mouse models as well as human ARPKD, renal cyst formation begins in utero and genetic background influences disease expression. Therefore, we hypothesize that these mammalian genes and their modifiers define a molecular pathway that is important in both renal cyst development and renal tubular differentiation. In this proposal, we will identify and characterize genes that influence the expression of the cpk mutation. Specifically, we will identify genes that accelerate the-development of renal cystic disease and cause bile duct plate abnormalities in the F2 affected progeny of an intersubspecific intercross between C57BL/6J-cpk/+ and Mus mus castaneus. In addition, we will map the bpk mutation, a second mouse model of human ARPKD. Then in a directed fashion, we will test whether the cpk genetic modifiers influence the phenotypic expression of the bpk mutation. Finally, we will construct congenic strains which isolate individual modifying loci in specific genetic backgrounds as the prelude to identifying and characterizing these genes. Therefore, this project will establish the molecular framework for identifying gene(s) that modify the disease pathogenesis in mouse recessive PKD. Our ultimate goal Is to use these genetic tools to dissect the molecular pathogenesis of human ARPKD.
