Regulation of Kidney-Specific Gene Expression
肾脏特异性基因表达的调控
基本信息
- 批准号:10743246
- 负责人:
- 金额:$ 30.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-11-18 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
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.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Peter Igarashi其他文献
Peter Igarashi的其他文献
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{{ truncateString('Peter Igarashi', 18)}}的其他基金
MicroRNA-Based Therapeutics for Rare Cystic Kidney Diseases
基于 MicroRNA 的罕见囊性肾病治疗方法
- 批准号:
7832043 - 财政年份:2009
- 资助金额:
$ 30.99万 - 项目类别:
MicroRNA-Based Therapeutics for Rare Cystic Kidney Diseases
基于 MicroRNA 的罕见囊性肾病治疗方法
- 批准号:
7936337 - 财政年份:2009
- 资助金额:
$ 30.99万 - 项目类别:
UT Southwestern O'Brien Kidney Research Core Center
德州大学西南奥布莱恩肾脏研究核心中心
- 批准号:
7883980 - 财政年份:2009
- 资助金额:
$ 30.99万 - 项目类别:
UT Southwestern O'Brien Kidney Research Core Center
德州大学西南奥布莱恩肾脏研究核心中心
- 批准号:
8148016 - 财政年份:2007
- 资助金额:
$ 30.99万 - 项目类别:
UT southwestern O'Brien Kidney Research Core Center
德克萨斯大学西南奥布莱恩肾脏研究核心中心
- 批准号:
8912182 - 财政年份:2007
- 资助金额:
$ 30.99万 - 项目类别:
UT Southwestern O'Brien Kidney Research Core Center
德州大学西南奥布莱恩肾脏研究核心中心
- 批准号:
8097975 - 财政年份:2007
- 资助金额:
$ 30.99万 - 项目类别:
UT Southwestern O'Brien Kidney Research Core Center
德州大学西南奥布莱恩肾脏研究核心中心
- 批准号:
7325171 - 财政年份:2007
- 资助金额:
$ 30.99万 - 项目类别:
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Kidney injury molecular(KIM-1)介导肾小管上皮细胞自噬在糖尿病肾病肾间质纤维化中的作用
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