The polycystic kidney diseases (PKD) are a group of disorders characterized by the presence of a large number of cysts throughout grossly enlarged kidneys. In humans, the diseases can be acquired or inherited in autosomal dominant (ADPKD) or autosomal recessive (ARPKD) forms. ADPKD is the most common, dominantly inherited kidney disease of man while ARPKD occurs relatively rarely. Clinically, ADPKD represents a major cause of chronic renal failure in man and it accounts for 10% of all patients requiring chronic dialysis or renal transplantation. The exact molecular lesion(s) of ADPKD are unknown and except for dialysis and transplantation, which are palliative, no curative treatment exists. DBA/2 mice homozygous for the pcy mutation develop a form of polycystic kidney disease with pathological phenotypes remarkably similar to the most prevalent form of autosomal dominant human polycystic kidney disease in man. The overall goal of this proposal is to use a combination of mouse genetics and positional cloning strategies to isolate the murine pcy gene and to elucidate the molecular basis of the mutation(s) in this gene responsible for the polycystic phenotype. The accompanying experimental planproposes to: 1) produce a DNA panel from 600 polycystic F2 animals in a pcy/pcy x Mus m. castaneus interspecific cross for pedigree analysis. This panel will have a resolution of 0.1 cM; 2) define RFLP for each of the 31 currently available genetic markers positioned in the region of mouse chromosome 9 containing the pcy locus; 3) perform pedigree analysis using the defined RFLPs to find markers that are linked to pcy at less than 0.1 cM; 4) produce P1 genomic and unidirectional cDNA libraries from DBA and pcy/pcy kidneys; 5) isolate and map 8-10 P1 clones corresponding to a 200 kb region encompassing the pcy gene by chromosome walking while searching for new RFLP within each clone; 6) search for genes in this 200 kb region; and 7) characterize and screen each candidate gene for characteristics consistent with the pcy polycystic kidney phenotype to identify the pcy gene.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045663-04
Application #
2144864
Study Section
General Medicine B Study Section (GMB)
Project Start
1992-09-30
Project End
1997-09-29
Budget Start
1995-09-30
Budget End
1996-09-29
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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