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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：
Peter Igarashi
金额：
$ 48.03万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
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：
https://reporter.nih.gov/project-details/10629391
关键词：
Ablation Adhesives Affect Binding Biochemical CHD4 gene Cell Proliferation Cells ChIP-seq Chromatin Loop Chromatin Remodeling Factor Complex Couples Cyclic AMP Cyst Cystic Kidney Diseases DNA DNA Binding Deposition Disease Distal EZH2 gene Enhancers Epithelial Cells Epithelium Fibrosis Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genomics Goals Growth Health Hi-C Histone Acetylation Histones Human Immunoprecipitation Individual Inherited Kidney Kidney Diseases Kidney Failure Ligands Mass Spectrum Analysis Measures Messenger RNA Molecular Mus Mutant Strains Mice Mutation Names NuRD complex Organ Pathogenesis Pathway interactions Phenotype Phosphorylation Play Polycomb Polycystic Kidney Diseases Polymerase Proteins RNA Polymerase II Regulation Renal function Repression Role Signal Pathway Signal Transduction Structure Testing Tissue-Specific Gene Expression Transcription Elongation Transcriptional Regulation Untranslated RNA Urinary tract WNT Signaling Pathway WNT9A gene Wnt proteins Work autosome beta catenin chromatin modification chromatin remodeling chromosome conformation capture congenital anomalies of the kidney derepression fibrogenesis gene repression genome-wide hepatocyte nuclear factor histone methylation histone modification improved in vivo evaluation indexing insight interstitial kidney cell kidney fibrosis lipid metabolism lymphoid enhancer-binding factor 1 mouse genetics mouse model mutant mutant mouse model nephrogenesis novel overexpression palmitoylation promoter recruit renal epithelium therapeutic target trafficking transcription factor transcriptome sequencing urinary

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：
Scientific reports
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：
Biochimica et biophysica acta
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：
Kidney international
影响因子：
19.6
作者：
通讯作者：

New insights into the role of HNF-1β in kidney (patho)physiology.

DOI：
10.1007/s00467-018-3990-7
发表时间：
2019-08
期刊：
Pediatric nephrology (Berlin, Germany)
影响因子：
0
作者：
Ferrè S;Igarashi P
通讯作者：
Igarashi P

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：
American journal of physiology. Renal physiology
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