The purpose of this MERIT extension is to continue our studies on hepatocyte nuclear factor-1? (HNF-1?) and its roles in kidney-specific gene expression, kidney development, and cystic kidney diseases. HNF-1? is a DNA-binding transcription factor that regulates tissue-specific gene expression in the kidney and other epithelial organs. Mutations of HNF-1? produce renal developmental abnormalities including renal agenesis, hypoplasia, cystic dysplasia, and glomerulocystic kidney disease. To unravel the pathogenesis of these anomalies, we have produced mutant mice that develop phenotypes similar to affected humans. Analysis of mutant mice has revealed that HNF-1? regulates the transcription of genes encoding ciliary proteins that are involved in human cystic kidney diseases. During the last project period, we used genomewide ChIP-seq combined with RNA expression profiling to identify additional transcriptional networks that are directly regulated by HNF-1?. Together with new mutant HNF-1? models, these studies uncovered novel roles of HNF-1? in the regulation of Wnt signaling, cAMP signaling, lipid metabolism, urinary concentration, and expression of noncoding RNAs. In the next project period we will extend this work to further unravel the functions of HNF-1? in the kidney.
Specific Aim 1 will use a combination of mouse genetics and mechanistic studies in cell culture to understand how HNF-1? regulates Wnt signaling, cAMP signaling, and other cystogenesis pathways. We will test the hypothesis that HNF-1? is a modifier gene in ADPKD by crossing HNF-1? mutant mice with kidney-specific Pkd1 and Pkd2 mutant mice.
Specific Aim 2 will elucidate the roles of HNF-1? in the regulation of two classes of noncoding RNAs, miRNAs and lncRNAs, which we have shown can play pathogenic roles in cystic kidney disease and EMT. We will determine whether genetic deletion or inhibition of noncoding RNAs that are overexpressed in HNF-1? mutant mice improves kidney function and structure. Collectively, the proposed studies will advance our understanding of normal kidney development, unravel how mutations of HNF-1? produce kidney diseases, and identify potential therapeutic targets for cystic and developmental diseases of the kidney.
The goal of this project is to understand the functions of a protein named HNF-1? in the kidney. Mutations of HNF-1? produce kidney cysts and renal failure in humans. The proposed studies are directed at understanding how cysts form and how they can be treated and prevented.
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