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（由申请人提供）：完全分化的细胞由其表达的基因以及最终的生理功能来定义，这种正常的基因表达模式或转录组在疾病状态下会发生改变，从而导致功能、生长受到干扰。问题是，在没有基因突变的情况下，这些异常的表达模式是如何建立和维持的？我们提出，基因组的表观遗传修饰和组蛋白甲基化会影响患病的基因表达变化。为了探索这一假设，我们必须首先了解胚胎发育过程中表观遗传修饰是如何在细胞谱系决定过程中被印记的，此前，PI 已将 Pax2 确定为肾上皮谱系中的关键 DNA 结合蛋白。然后发现 PTIP 作为衔接蛋白，将 Pax2 连接到组蛋白甲基化复合物，从而在靶基因上印上阳性表观遗传标记。在本应用中，Aim 1 将使用下一代染色质免疫沉淀法。测序，以及基因改造小鼠的特定品系，以绘制 Pax2/PTIP 与基因组相互作用的位点，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。在目标 2 中，我们将定义 PTIP 和组蛋白甲基化在肾间质纤维化中的作用，并将其与已知介导纤维化的 TGF-β 信号通路联系起来。鉴于癌症和其他疾病状态中表观遗传变化的许多相关性，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侵害的情况下直接引发疾病状态，我们的初步数据强烈表明它们可以。