Project Details
Description
ABSTRACT
The purpose of this MERIT renewal is to continue our studies on hepatocyte nuclear factor-1β (HNF-1β) and its
roles in kidney-specific gene expression and cystic kidney diseases. HNF-1β is a DNA-binding transcription
factor that regulates tissue-specific gene expression in the kidney and other epithelial organs. Mutations of HNF-
1β produce congenital anomalies of the kidney and urinary tract, cystic kidney disease, autosomal dominant
tubulointerstitial kidney disease, and inherited tubulopathies. To unravel the pathogenesis of these disorders,
we have produced HNF-1β mutant mice that develop phenotypes similar to those seen in affected humans.
Analysis of the mutant mice has revealed that HNF-1β plays a central role in the expression of polycystic kidney
disease genes, such as PKD2 and PKHD1. During the last project period, we used genome-wide ChIP-seq and
RNA-seq to identify transcriptional networks that are directly regulated by HNF-1β. Together with new mutant
mouse models, these studies uncovered novel roles of HNF-1β in the regulation of Wnt signaling, cAMP
signaling, lipid metabolism, urinary concentration, and expression of noncoding RNAs. Preliminary studies using
mass spectrometry revealed that HNF-1β interacts with proteins involved in chromatin remodeling, histone
modification, and transcription elongation. In the next project period we will extend this work to further unravel
the functions of HNF-1β in the kidney. Specific Aim 1 will use biochemical studies to unravel the molecular
mechanisms whereby HNF-1β represses Wnt pathway genes. We will test the hypothesis that HNF-1β forms
repressive chromatin loops that exert long-range effects on histone modification, chromatin remodeling, and
transcription elongation. Specific Aim 2 will apply mouse genetics to elucidate the roles of dysregulated Wnt
signaling in the HNF-1β mutant phenotype. We will determine whether mutations of Wnt pathway genes that are
overexpressed in HNF-1β mutant mice improve kidney function and structure. Collectively, the proposed studies
will advance our understanding of gene regulation, unravel how mutations of HNF-1β produce kidney
abnormalities, and identify potential therapeutic targets for HNF-1β-related cystic kidney diseases.
Status | Active |
---|---|
Effective start/end date | 4/15/91 → 6/30/24 |
Funding
- National Institute of Diabetes and Digestive and Kidney Diseases: $306,265.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $312,516.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $280,800.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $466,717.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $480,257.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $309,891.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $92,600.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $303,202.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $220,826.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $280,800.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $280,800.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $321,850.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $280,800.00
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