Regulation of Kidney-Specific Gene Expression

肾脏特异性基因表达的调节

基本信息

  • 批准号:
    10629391
  • 负责人:
  • 金额:
    $ 48.03万
  • 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

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(51)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Multiomics analysis reveals that hepatocyte nuclear factor 1β regulates axon guidance genes in the developing mouse kidney.
多组学分析表明,肝细胞核因子1β调节发育中的小鼠肾脏中的轴突引导基因。
  • DOI:
    10.1038/s41598-022-22327-5
  • 发表时间:
    2022-10-20
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
  • 通讯作者:
Cloning, sequence, and tissue distribution of a rabbit renal Na+/H+ exchanger transcript.
兔肾 Na /H 交换转录物的克隆、序列和组织分布。
  • DOI:
    10.1016/0167-4781(91)90221-7
  • 发表时间:
    1991
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Hildebrandt,F;Pizzonia,JH;Reilly,RF;Rebouças,NA;Sardet,C;Pouysségur,J;Slayman,CW;Aronson,PS;Igarashi,P
  • 通讯作者:
    Igarashi,P
Tubule-specific ablation of endogenous β-catenin aggravates acute kidney injury in mice.
内源性β-连环蛋白的肾小管特异性消融会加重小鼠急性肾损伤
  • DOI:
    10.1038/ki.2012.173
  • 发表时间:
    2012-09
  • 期刊:
  • 影响因子:
    19.6
  • 作者:
  • 通讯作者:
New insights into the role of HNF-1β in kidney (patho)physiology.
Tissue-specific regulation of the mouse Pkhd1 (ARPKD) gene promoter.
小鼠 Pkhd1 (ARPKD) 基因启动子的组织特异性调控。
  • DOI:
    10.1152/ajprenal.00422.2013
  • 发表时间:
    2014
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Williams,ScottS;Cobo-Stark,Patricia;Hajarnis,Sachin;Aboudehen,Karam;Shao,Xinli;Richardson,JamesA;Patel,Vishal;Igarashi,Peter
  • 通讯作者:
    Igarashi,Peter
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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

Regulation of Kidney-Specific Gene Expression
肾脏特异性基因表达的调控
  • 批准号:
    10743246
  • 财政年份:
    2022
  • 资助金额:
    $ 48.03万
  • 项目类别:
Regulation of Kidney-Specific Gene Expression
肾脏特异性基因表达的调节
  • 批准号:
    9318506
  • 财政年份:
    2016
  • 资助金额:
    $ 48.03万
  • 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:
    7832043
  • 财政年份:
    2009
  • 资助金额:
    $ 48.03万
  • 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:
    $ 48.03万
  • 项目类别:
Regulation of kidney-Specific Gene Expression
肾脏特异性基因表达的调节
  • 批准号:
    7988995
  • 财政年份:
    2009
  • 资助金额:
    $ 48.03万
  • 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:
    $ 48.03万
  • 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:
    $ 48.03万
  • 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:
    $ 48.03万
  • 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:
    $ 48.03万
  • 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:
    $ 48.03万
  • 项目类别:

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