Epigenetic Regulation of Kidney Development

肾脏发育的表观遗传调控

• 批准号: 8845192
• 负责人: Gregory R Dressler
• 金额: $ 33.82万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8845192
• 关键词: Acute; Adaptor Signaling Protein; Address; Adult; Affect; Aging; Animal Model; Binding; Cell Lineage; Cell physiology; Cells; Chromatin; Chronic; Chronic Disease; Chronic Kidney Failure; Clinical; Communication; Complex; Cues; DNA Sequence; DNA Sequence Alteration; DNA-Binding Proteins; Data; Decision Making; Development; Disease; Embryo; Embryonic Development; Epigenetic Process; Epithelial; Epithelial Cells; Fibrosis; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Models; Genetic Transcription; Genome; Growth; Intervention; Investigation; Investments; Kidney; Kidney Diseases; Lead; Life; Link; Maintenance; Malignant Neoplasms; Maps; Mediating; Mendelian disorder; Modification; Mus; Mutation; Nuclear; Pathway interactions; Pattern; Phenotype; Physiological; Population; Proteins; Public Health; Recruitment Activity; Role; Signal Pathway; Signal Transduction; Site; Specific qualifier value; Specificity; Stem cells; Stress; Testing; Time; Tissues; Trans-Activators; Work; base; cell type; chromatin immunoprecipitation; developmental plasticity; disease phenotype; embryonic stem cell; epigenetic regulation; genome analysis; genome wide association study; genome-wide linkage; histone methylation; human disease; imprint; in vivo Model; innovation; insight; interstitial; kidney cell; kidney epithelial cell; loss of function; methylation pattern; nephrogenesis; next generation sequencing; renal epithelium; research study; therapeutic development; tool

DESCRIPTION (provided by applicant): A fully differentiated cell is defined by the genes it expresses and, ultimately, by its physiological functions. This normal pattern of gene expression, or transcriptome, is altered in a diseased state such that function is perturbed, growth is deregulated, and communication with other cells affected. The question is, how are these abnormal expression patterns established and maintained in the absence of genetic mutations? We propose that epigenetic modifications on the genome, and specifically histone methylation, impact gene expression changes in diseased tissues. To explore this hypothesis, we must first understand how epigenetic modifications are imprinted during development of the embryo, as cell lineages decisions are made. Previously, the PI has identified Pax2 as a critical DNA binding protein in the renal epithelial lineage. The lab then discovered PTIP as an adaptor protein that links Pax2 to a histone methylation complex to imprint positive epigenetic marks on target genes. In this application, Aim 1 will use chromatin immunoprecipitation, next generation sequencing, and specific strains of genetically altered mice to map the sites of Pax2/PTIP interactions with the genome and to correlate this with gene expression patterns. Furthermore, we have the first real evidence that altering a histone methylation pathway in a cell specific manner can lead to chronic renal disease. In Aim 2, we will define the role of PTIP and histone methylation in renal interstitial fibrosis and correlate this with TGF-ß signaling pathways that are known to mediate fibrosis. While there are many correlations of epigenetic changes in cancer and other disease states, our studies will address for the first time whether epigenetic modifications can directly initiate a disease state in the absence of other mutations or environmental insults. Our preliminary data strongly suggests that they can.

描述（由适用提供）：一个完全不同的细胞由它表达的基因定义，最终由其物理功能定义。这种基因表达或转录组的正常模式在解散状态下发生了改变，因此功能受到干扰，生长受管制，并与受影响的其他细胞进行通信。问题是，在没有通用突变的情况下，如何建立和维持这些异常表达模式？我们建议对基因组，特别是组蛋白甲基化的表观遗传修饰影响基因表达在解剖组织中的变化。为了探讨这一假设，我们必须首先了解在胚胎的发展过程中如何印刷表观遗传修饰，因为您做出了细胞谱系的决策。以前，PI已将PAX2鉴定为肾上皮谱系中的临界DNA结合蛋白。然后，该实验室发现PTIP是一种衔接蛋白，将PAX2与组蛋白甲基化复合物联系起来与靶基因上的阳性表观遗传标记。在此应用中，AIM 1将使用染色质免疫沉淀，下一代测序以及遗传改变的小鼠的特定菌株来绘制PAX2/PTIP相互作用的位点与基因组的位点，并将其与基因表达模式相关联。此外，我们有第一个真正的证据表明，以细胞特异性方式改变组蛋白甲基化途径可以导致慢性肾脏疾病。在AIM 2中，我们将定义PTIP和组蛋白甲基化在肾纤维化中的作用，并将其与已知可以介导纤维化的TGF-ß信号通路相关。尽管癌症和其他疾病状态的表观遗传变化有许多相关性，但我们的研究将首次解决表观遗传修饰是否可以在没有其他突变或环境事件的情况下直接引发疾病状态。我们的初步数据强烈表明他们可以。