The overall aim of this proposal is to determine the role of the homeobox gene Cux-1 in cell cycle regulation in the kidney. Cux-1 is the murine homologue of the Drosophila gene Cut, which is required for the proper development of the Malpighian tubules, the insect excretory and osmoregulatory organs. Mammalian Cut homologues function as transcriptional repressors of genes specifying terminal differentiation in multiple cell lineages. Cux-1 is part of the network controlling G1-S transition, where it represses the expression of the cyclin kinase inhibitor (CKI) p21 in S phase. Recent studies demonstrate that deregulation of Cux-1 in transgenic mice results in down regulation of p27kip1 expression during nephrogenesis, renal hyperplasia, and mesangial cell proliferation. Mesangial cell proliferation is linked to matrix accumulation and precedes the development of glomeruloscierosis. The proposed studies will test the hypotheses that Cux-1 regulates cell proliferation during normal renal development, and that dereguletion of Cux-1 contributes to immune mediated and non-immune mediated renal injury.
The specific aims are: (I) Perform morphological and physiological evaluations of developing kidneys in transgenic mice constitutively expressing Cux-1; (ii) perform studies on primary mesangial cells isolated from wild type and transgenic kidneys to determine whether PDGF and bFGF induced down regulation of the CKI p27 is mediated by Cux-1; (iii) evaluate whether Cux-1 binds to the p27 promoter, and determine whether Cux-1 represses p27 gene expression; (iv) determine if Cux-1 represses p21 and/or p27 during renal inflammatory injury, and whether this results in a further diminution of renal function. These studies will provide novel insights into the mechanisms of cell proliferation in renal disease, and may provide future therapeutic strategies for renal disease.
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