Regulation of kidney-Specific Gene Expression

肾脏特异性基因表达的调节

• 批准号: 7324087
• 负责人: Peter Igarashi
• 金额: $ 30.63万
• 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 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7324087
• 关键词: Animal Model; Autosomal Recessive Polycystic Kidney; Binding Sites; Biochemical; Biological Assay; C-terminal; Cell Differentiation process; Child; Chromatin Structure; Cyst; Cystic Kidney Diseases; Cystic kidney; DNA Binding; Development; Down-Regulation; Duct (organ) structure; Epithelial; Exhibits; Family; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Recombination; Genetic Transcription; Genitourinary system; Goals; Histone Acetylation; Histones; Human; Infant; Kidney; Kidney Failure; Knock-in Mouse; LacZ Genes; Ligase; Link; Liver; Location; Lysine; Maps; Measures; Mediating; Microarray Analysis; Modification; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Organ; Organogenesis; PKHD1 gene; Pancreas; Pathogenesis; Pattern; Phenotype; Process; Proteins; Regulation; Regulatory Element; Reporter Genes; Research Personnel; Role; Site; Testing; Tissue-Specific Gene Expression; Tissues; Transcriptional Activation; Transcriptional Activation Domain; Transgenic Mice; Transgenic Organisms; Ubiquitin; Ubiquitin-Conjugating Enzymes; Ubiquitination; Yeasts; bile duct; chicken DcoHalpha protein; deletion analysis; disease phenotype; hepatocyte nuclear factor; histone acetyltransferase; homeodomain; in vivo; inhibitor/antagonist; insight; kidney cell; mutant; nephrogenesis; novel; programs; promoter; transcription factor; ubiquitin ligase; yeast two hybrid system

The overall goal of this project is to understand the roles of hepatocyte nuclear factor-13 (HNF-1(3)in kidney-specific gene expression, renal cell differentiation, and kidney organogenesis. HNF-1(3belongs to a family of homeodomain-containing transcription factors that regulate tissue-specific gene expression in the kidney, liver, pancreas, and other organs. Humans with mutations of HNF-13 develop maturity-onset diabetes of the young type 5 (MODY5) and congenital cystic abnormalities of the kidney. Transgenic mice expressing mutant HNF-13 under the control of a kidney-specific promoter develop kidney cysts and renal failure, which is similar to the phenotype of humans with MODY5. Similarly, kidney-specific deletion of HNF- 1(3 using Cre/loxP recombination results in renal cyst formation. HNF-1{3mutant mice show decreased expression of Pkhdl, the gene mutated in autosomal recessive polycystic kidney disease (ARPKD), and HNF-13 directly regulates the Pkhdl promoter. These studies identify Pkhdl as a novel gene target of HNF- 13 in the kidney. They establish a previously unrecognized link between two renal cystic diseases, MODY5 and ARPKD, and suggest that the mechanism of cyst formation in humans with MODY5 involves down- regulation of PKHD1 gene expression. To test this hypothesis and to further define the functions of HNF-13 in the kidney, we will complete the following specific aims: 1. Define the roles of coactivators and histone acetylation in the regulation of Pkhdl gene transcription. 2. Determine how the activity of HNF-13 is reciprocally regulated by SUMO ligases and ubiquitin ligases. 3. Determine how HNF-13 regulates the tissue-specific expression of Pkhdl in the kidney and liver. 4. Elucidate the molecular pathogenesis of the kidney and genitourinary tract abnormalities caused by mutations of HNF-13. The proposed studies will utilize genetically-modified mice to define in vivo expression patterns and disease phenotypes and biochemical studies to elucidate molecular mechanisms. Understanding the functions of HNF-13 and the regulation of Pkhdl gene transcription will provide insights into the pathogenesis of congenital kidney abnormalities and ARPKD,which is one of the most common genetic causes of renal failure in infants and children.

本项目的总体目标是了解肝细胞核因子-13(HNF-1(3))在 肾脏特异基因表达、肾细胞分化和肾脏器官发生。HNF-1(3属于 含有同源结构域的转录因子家族，调节组织特异性基因的表达 肾、肝、胰腺和其他器官。携带HNF-13突变的人类出现成熟期 年轻的5型糖尿病(MODY5)和先天性肾脏囊性异常。转基因小鼠 在肾脏特异性启动子控制下表达突变型HNF-13可发展为肾囊肿和肾脏 失败，这类似于患有MODY5的人类的表型。类似地，肾脏特异性缺失HNF- 1(3)使用Cre/loxP重组可导致肾囊肿形成。HNF-1{3突变小鼠表现为减少 常染色体隐性遗传性多囊肾病中突变基因Pkhd1的表达 HNF-13直接调控Pkhd1启动子。这些研究确定Pkhd1是HNF-1的一个新的基因靶点。 肾中13例。他们在两种肾囊性疾病之间建立了一种以前未被发现的联系，MODY5 和ARPKD，并提示MODY5患者的包囊形成机制涉及向下- PKHD1基因表达的调控。为了验证这一假说并进一步定义HNF-13的功能 在肾脏方面，我们将完成以下具体目标： 1.明确共激活因子和组蛋白乙酰化在Pkhd1基因转录调控中的作用。 2.确定HNF-13的活性如何受相扑连接酶和泛素连接酶的相互调节。 3.确定HNF-13如何调节Pkhd1在肾脏和肝脏中的组织特异性表达。 4.阐明肾及泌尿生殖道异常的分子发病机制 人类神经营养因子-13的突变。 拟议的研究将利用转基因小鼠来定义体内表达模式和 疾病表型和生化研究以阐明分子机制。了解 HNF-13的功能和Pkhd1基因转录的调节将为深入了解 先天性肾脏异常的发病机制和ARPKD，这是最常见的遗传因素之一 婴儿和儿童肾功能衰竭的原因。