The understanding of cellular growth and differentiation during kidney development offers promise for novel treatments of kidney disease and of prevention and is an area of considerable present excitement. This application proposes to identify zinc finger transcription factors whose expression may regulate early nephrogenesis. The focus will be on KZF- 1 (kidney zinc finger- 1), a novel zinc finger protein whose expression is modulated in nephrogenesis. Additionally, the application proposes to screen for other similar proteins from a kidney blastemal cell library.
The specific aims are: (1) To study the structure and function of KZF-1 by in situ hybridization and immunocytochemical analysis of its cellular expression during renal development, determination of a target DNA sequence to which KZF-1 binds, definition of domains important in nuclear localization, DNA binding, transactivation, and/or transrepression, and investigation of the role of KZF-1 in kidney differentiation in an organ culture model. (2) To identify novel zinc finger cDNAs from a blastemal cell library and screen for those whose expression is modulated in early nephrogenesis. Studies proposed in this application are likely to lead to a better molecular definition of nephrogenesis through a delineation of transcription factor cascades that control kidney growth and differentiation. The latter goal will ultimately be accomplished by identification of the regulators of these regulatory genes and by isolation of target genes whose expression these transcription factors control. Insights resulting from such work may have impact on the treatment of renal disease characterized by abnormal growth or development or those in which acute or chronic nephron injury occurs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045617-03
Application #
3247109
Study Section
General Medicine B Study Section (GMB)
Project Start
1992-09-30
Project End
1997-09-29
Budget Start
1993-09-30
Budget End
1994-09-29
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
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Scholz, H; Bossone, S A; Cohen, H T et al. (1997) A far upstream cis-element is required for Wilms' tumor-1 (WT1) gene expression in renal cell culture. J Biol Chem 272:32836-46
Cohen, H T; Bossone, S A; Zhu, G et al. (1997) Sp1 is a critical regulator of the Wilms' tumor-1 gene. J Biol Chem 272:2901-13
Drummond, I A; Goodyer, P; Sukhatme, V P (1997) Immortal, developmentally arrested human fetal kidney cell lines created by retroviral expression of human papilloma virus E6 and E7. Exp Nephrol 5:390-8
Zhu, G; Nicolson, A G; Cowley, B D et al. (1996) In vivo adenovirus-mediated gene transfer into normal and cystic rat kidneys. Gene Ther 3:298-304
Rupprecht, H D; Drummond, I A; Madden, S L et al. (1994) The Wilms' tumor suppressor gene WT1 is negatively autoregulated. J Biol Chem 269:6198-206
Drummond, I A; Rupprecht, H D; Rohwer-Nutter, P et al. (1994) DNA recognition by splicing variants of the Wilms' tumor suppressor, WT1. Mol Cell Biol 14:3800-9