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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK051034-01
Application #
2152133
Study Section
Special Emphasis Panel (SRC (02))
Project Start
1995-09-30
Project End
1999-08-31
Budget Start
1995-09-30
Budget End
1996-08-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Guay-Woodford, L M; Green, W J; Lindsey, J R et al. (2000) Germline and somatic loss of function of the mouse cpk gene causes biliary ductal pathology that is genetically modulated. Hum Mol Genet 9:769-78
Nauta, J; Goedbloed, M A; Herck, H V et al. (2000) New rat model that phenotypically resembles autosomal recessive polycystic kidney disease. J Am Soc Nephrol 11:2272-84
Mrug, M; Stockwin, J; Wuthrich, R P et al. (2000) Mapping of mouse alpha 1(XIII) collagen to chromosome 10 and its exclusion as a kd candidate gene. Biochem Genet 38:337-40
Guay-Woodford, L M (1999) Overview: the genetics of renal disease. Semin Nephrol 19:312-8
Guay-Woodford, L M (1999) Phenotypic variability in PKD1: the family as a starting point. Kidney Int 56:344-6
Zerres, K; Mucher, G; Becker, J et al. (1998) Prenatal diagnosis of autosomal recessive polycystic kidney disease (ARPKD): molecular genetics, clinical experience, and fetal morphology. Am J Med Genet 76:137-44
Guay-Woodford, L M; Galliani, C A; Musulman-Mroczek, E et al. (1998) Diffuse renal cystic disease in children: morphologic and genetic correlations. Pediatr Nephrol 12:173-82
Sharp, C K; Bergman, S M; Stockwin, J M et al. (1997) Dominantly transmitted glomerulocystic kidney disease: a distinct genetic entity. J Am Soc Nephrol 8:77-84
Guay-Woodford, L M; Bryda, E C; Christine, B et al. (1996) Evidence that two phenotypically distinct mouse PKD mutations, bpk and jcpk, are allelic. Kidney Int 50:1158-65