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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：
9318506
负责人：
Peter Igarashi
金额：
$ 36.59万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-25 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9318506
关键词：
Adenylate Cyclase Adopted Affect Alleles Area Autosomal Dominant Polycystic Kidney Award C-terminal CRISPR/Cas technology Cadherins Cell Culture Techniques Cell Line Cells ChIP-seq Cilia Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Complex Congenital Abnormality Contact Inhibition Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyst Cystic Kidney Diseases Cystic kidney DNA DNA Binding Development Digestion Disease Dominant-Negative Mutation Dysplasia Embryo Epithelial Epithelial Cells Epithelium Exhibits Exons Fibrosis Fostering GLIS2 gene Gene Activation Gene Expression Gene Proteins Gene Targeting Generations Genes Genetic Genetic Crosses Genetic Models Genetic Transcription Genotype Goals Growth Human Immunoblot Analysis In Vitro Instruction Kidney Kidney Diseases Kidney Failure Knock-out Knockout Mice Length Malignant Neoplasms Mammalian Oviducts Measures Metabolism MicroRNAs Mifepristone Modeling Molecular Profiling Morphology Mothers Mus Mutant Strains Mice Mutation NIH 3T3 Cells Names Nucleotides Null Lymphocytes Organ Other Genetics PKD2 protein Pathogenesis Pathogenicity Pathway Analysis Pathway interactions Phenotype Phosphorylation Physiology Plasmids Play Progress Reports Proteins Publishing Quantitative Reverse Transcriptase PCR Reagent Regulation Renal function Reverse Transcriptase Polymerase Chain Reaction Role Severities Signal Transduction Site Southern Blotting Structure TCF3 gene Testing Time Tissue-Specific Gene Expression Tissues Transcriptional Activation UMOD gene Untranslated RNA Up-Regulation WNT Signaling Pathway Work base c new c-myc Genes genetic manipulation genome-wide hepatic nuclear factor 1 hepatocyte nuclear factor improved kidney cell knock-down lipid metabolism loss of function mutation migration mouse model mutant nephrogenesis new therapeutic target novel overexpression phosphoric diester hydrolase prevent programs promoter protein expression renal agenesis targeted treatment therapeutic target transcription factor transcriptome sequencing urinary zygote

项目摘要

DESCRIPTION (provided by applicant): The purpose of this competitive renewal application is to continue our ongoing studies on hepatocyte nuclear factor-1β (HNF-1β) and its roles in the regulation of 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 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. Kidney-specific inactivation of HNF-1β or expression of dominant-negative mutant HNF-1β in transgenic mice produces kidney cysts and renal failure. Analysis of these mutant mice has revealed that HNF-1β regulates the transcription of genes encoding ciliary proteins that are involved in human cystic kidney diseases. These findings demonstrate that HNF-1β plays a central role in cystic and developmental diseases of the kidney. To further elucidate the functions of HNF-1β, the proposed studies have two specific aims. The first aim is to understand how HNF-1β regulates Wnt signaling. Preliminary studies have shown that HNF-1β regulates genes that are involved in Wnt signaling, and inhibition of HNF-1β results in abnormal activation of the Wnt pathway, which may underlie cyst formation. Studies will be performed in mutant mice, cultured cells, and organ culture to elucidate the mechanism of activation of Wnt signaling. The second aim is to characterize microRNAs that are regulated by HNF-1β in the kidney. In addition to protein-coding genes, HNF-1β regulates the expression of microRNAs, which are small non-coding RNAs that regulate post-transcriptional gene expression. These findings have revealed a novel pathway by which HNF-1β regulates tissue-specific gene expression and kidney development. The functions of two families of microRNAs that are regulated by HNF-1β will be studied, and their target mRNA transcripts will be identified. Collectively, the proposed studies will advance our understanding of normal kidney development, unravel how mutations of HNF-1β produce kidney diseases, and identify potential therapeutic targets for cystic and developmental diseases of the kidney.

描述（由申请人提供）：本竞争性续展申请的目的是继续我们正在进行的关于肝细胞核因子-1β（HNF-1β）及其在肾脏特异性基因表达和囊性肾病调节中的作用的研究。 HNF-1β 是一种 DNA 结合转录因子，可调节肾脏和其他上皮器官中的组织特异性基因表达。 HNF-1β 突变会导致肾脏发育异常，包括肾发育不全、发育不全、囊性发育不良和肾小球囊性肾病。为了揭示这些异常的发病机制，我们培育了突变小鼠，它们的表型与受影响的人类相似。转基因小鼠中 HNF-1β 的肾脏特异性失活或显性失活突变体 HNF-1β 的表达会产生肾囊肿和肾衰竭。对这些突变小鼠的分析表明，HNF-1β 调节编码与人类囊性肾病有关的纤毛蛋白的基因的转录。这些发现表明 HNF-1β 在肾脏囊性和发育性疾病中发挥着核心作用。为了进一步阐明 HNF-1β 的功能，拟议的研究有两个具体目标。第一个目标是了解 HNF-1β 如何调节 Wnt 信号传导。初步研究表明，HNF-1β 调节参与 Wnt 信号传导的基因，抑制 HNF-1β 会导致 Wnt 通路异常激活，这可能是囊肿形成的基础。将在突变小鼠、培养细胞和器官培养物中进行研究，以阐明 Wnt 信号传导的激活机制。第二个目标是表征肾脏中受 HNF-1β 调节的 microRNA。除了蛋白质编码基因外，HNF-1β 还调节 microRNA 的表达，microRNA 是调节转录后基因表达的小非编码 RNA。这些发现揭示了 HNF-1β 调节组织特异性基因表达和肾脏发育的新途径。我们将研究 HNF-1β 调控的两个 microRNA 家族的功能，并鉴定它们的靶 mRNA 转录本。总的来说，拟议的研究将增进我们对正常肾脏发育的理解，揭示 HNF-1β 突变如何产生肾脏疾病，并确定肾脏囊性和发育性疾病的潜在治疗靶点。