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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK051068-01
Application #
2152180
Study Section
Special Emphasis Panel (SRC (02))
Project Start
1995-09-30
Project End
1996-08-31
Budget Start
1995-09-30
Budget End
1996-08-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Lockheed Martin Energy Systems, Inc.
Department
Type
DUNS #
City
Oak Ridge
State
TN
Country
United States
Zip Code
37831
Zhang, Qihong; Murcia, Noel S; Chittenden, Laura R et al. (2003) Loss of the Tg737 protein results in skeletal patterning defects. Dev Dyn 227:78-90
Brown, Nicole E; Murcia, Noel S (2003) Delayed cystogenesis and increased ciliogenesis associated with the re-expression of polaris in Tg737 mutant mice. Kidney Int 63:1220-9
Nakanishi, K; Sweeney Jr, W E; Avner, E D et al. (2001) Expression of the orpk disease gene during kidney development and maturation. Pediatr Nephrol 16:219-26
Nakanishi, K; Sweeney Jr, W E; Zerres, K et al. (2000) Proximal tubular cysts in fetal human autosomal recessive polycystic kidney disease. J Am Soc Nephrol 11:760-3
Sweeney, W E; Chen, Y; Nakanishi, K et al. (2000) Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor. Kidney Int 57:33-40
Murcia, N S; Richards, W G; Yoder, B K et al. (2000) The Oak Ridge Polycystic Kidney (orpk) disease gene is required for left-right axis determination. Development 127:2347-55
Sweeney, W E; Futey, L; Frost, P et al. (1999) In vitro modulation of cyst formation by a novel tyrosine kinase inhibitor. Kidney Int 56:406-13
Avner, E D; Woychik, R P; Dell, K M et al. (1999) Cellular pathophysiology of cystic kidney disease: insight into future therapies. Int J Dev Biol 43:457-61
Sweeney Jr, W E; Avner, E D (1998) Functional activity of epidermal growth factor receptors in autosomal recessive polycystic kidney disease. Am J Physiol 275:F387-94
Orellana, S A; Avner, E D (1998) Cell and molecular biology of kidney development. Semin Nephrol 18:233-43

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