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UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER AT DALLAS

The purpose of this Recovery Act Administrative Supplement is to accelerate the pace of research on the parent NIH grant 5R01DK042921-17 entitled ?Regulation of Kidney-Specific Gene Expression.? The goal of the parent grant is to understand the roles of the transcription factor HNF-1? in kidney-specific gene expression and inherited cystic kidney diseases. The supplement will accelerate studies proposed under Specific Aim 4, ?Elucidate the molecular pathogenesis of the kidney and GU tract abnormalities caused by mutations of HNF-1?.? One objective of these studies is to identify and characterize additional HNF-1? gene targets in the kidney using cDNA microarray analysis. Recently, in a derivative project that falls within the scope of specific aim 4, we have used genome-wide chromatin immunoprecipitation (ChIP)-on-chip to identify HNF-1? target genes in renal epithelial cells. This effort has been highly successful and revealed that HNF-1? plays a central role in the regulation of multiple cystic disease genes as well as novel target genes such as SOCS3 and Kif12. In addition, analysis of HNF-1? mutant cells using microRNA arrays has revealed that HNF-1? regulates the expression of a subset of microRNAs that may be involved in the post-transcriptional expression of human cystic disease genes. The proposed supplement will extend these promising findings. First, a complementary ChIP-seq approach will be used to identify additional HNF-1? target genes that were not detected using ChIP-on-chip. Second, microRNAs that are regulated by HNF-1? and dysregulated in HNF-1? mutant mice will be identified. Accomplishing these goals is feasible within the proposed timeframe of the supplement. Collectively, these studies will help to unravel the genetic networks that are disrupted in humans with congenital kidney malformations caused by mutations of HNF-1?. The supplement will allow for job creation through the recruitment and retention of experienced research personnel. The tempo of scientific research will be accelerated through the introduction of new technologies to advance the goals of the parent grant.

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