Regulation of Kidney-Specific Gene Expression

肾脏特异性基因表达的调控

• 批准号: 8516005
• 负责人: Peter Igarashi
• 金额: $ 33.37万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516005
• 关键词: Address; Affect; Autosomal Dominant Polycystic Kidney; Cell Polarity; Cell Proliferation; Cell Proliferation Regulation; Cell division; ChIP-on-chip; ChIP-seq; Code; Cultured Cells; Cyst; Cystic Kidney Diseases; Cystic kidney; DNA Binding; DNA Sequence; Development; Diabetes Mellitus; Disease; Dominant-Negative Mutation; Dysplasia; Embryonic Development; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Family; Fetal Ultrasonography; Fibrosis; Functional RNA; Gene Expression; Genes; Genetic Transcription; Genitourinary system; Germ-Line Mutation; Goals; Homeodomain Proteins; Human; Kidney; Kidney Diseases; Kidney Failure; Knock-out; Link; Loss of Heterozygosity; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Messenger RNA; MicroRNAs; Molecular; Molecular Profiling; Mutant Strains Mice; Mutate; Mutation; Names; Organ; Organ Culture Techniques; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Proteins; Regulation; Renal carcinoma; Renal tubule structure; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Tissue-Specific Gene Expression; Tissues; Transcript; Transgenic Mice; clinically significant; genome wide association study; genome-wide; hepatocyte nuclear factor; inhibitor/antagonist; mouse model; mutant; nephrogenesis; new therapeutic target; novel; pre-clinical; promoter; small molecule; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): The purpose of this competitive renewal application is to continue our ongoing studies on hepatocyte nuclear factor-1¿ (HNF-1¿) and its roles in the regulation of kidney-specific gene expression and cystic kidney diseases. HNF-1¿ is a DNA-binding transcription factor that regulates tissue-specific gene expression in the kidney and other epithelial organs. Mutations of HNF-1¿ 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-1¿ or expression of dominant-negative mutant HNF-1¿ in transgenic mice produces kidney cysts and renal failure. Analysis of these mutant mice has revealed that HNF-1¿ regulates the transcription of genes encoding ciliary proteins that are involved in human cystic kidney diseases. These findings demonstrate that HNF-1¿ plays a central role in cystic and developmental diseases of the kidney. To further elucidate the functions of HNF-1¿, the proposed studies have two specific aims. The first aim is to understand how HNF-1¿ regulates Wnt signaling. Preliminary studies have shown that HNF-1¿ regulates genes that are involved in Wnt signaling, and inhibition of HNF-1¿ 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-1¿ in the kidney. In addition to protein-coding genes, HNF-1¿ 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-1¿ regulates tissue-specific gene expression and kidney development. The functions of two families of microRNAs that are regulated by HNF-1¿ 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-1¿ produce kidney diseases, and identify potential therapeutic targets for cystic and developmental diseases of the kidney.

描述（由申请人提供）：本竞争性更新申请的目的是继续我们正在进行的肝细胞核因子-1 （HNF-1）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-1是一种dna结合转录因子，可调节肾脏和其他上皮器官中组织特异性基因的表达。HNF-1基因突变可导致肾脏发育异常，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。为了解开这些异常的发病机制，我们已经产生了突变小鼠，其表型与受影响的人类相似。在转基因小鼠中，肾特异性的HNF-1¿失活或显性阴性突变体HNF-1¿的表达会产生肾囊肿和肾功能衰竭。对这些突变小鼠的分析表明，HNF-1¿调节与人类囊性肾病有关的纤毛蛋白编码基因的转录。这些发现表明，HNF-1¿在肾脏的囊性和发育性疾病中起着核心作用。为了进一步阐明HNF-1¿的功能，拟议的研究有两个具体目的。第一个目标是了解HNF-1如何调节Wnt信号。初步研究表明，HNF-1¿调节参与Wnt信号传导的基因，抑制HNF-1¿会导致Wnt通路的异常激活，这可能是囊肿形成的基础。研究将在突变小鼠、培养细胞和器官培养中进行，以阐明Wnt信号激活的机制。第二个目标是表征肾脏中受HNF-1调控的microrna。除了蛋白质编码基因外，HNF-1还调节microRNAs的表达，microRNAs是一种调节转录后基因表达的小非编码rna。这些发现揭示了HNF-1调节组织特异性基因表达和肾脏发育的新途径。将研究受HNF-1调控的两个microrna家族的功能，并鉴定它们的靶mRNA转录物。总的来说，拟议的研究将促进我们对正常肾脏发育的理解，揭示HNF-1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。