Epigenetic Regulation of Kidney Development

肾脏发育的表观遗传调控

• 批准号: 9381814
• 负责人: Gregory R Dressler
• 金额: $ 34.63万
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381814
• 关键词: Abnormal Cell; Acute; Acute Disease; Acute Renal Failure with Renal Papillary Necrosis; Adaptor Signaling Protein; Address; Adult; Animals; Cell Death; Cell Lineage; Cell Proliferation; Cell physiology; Cells; Chromatin; Chronic; Chronic Disease; Chronic Kidney Failure; Complex; Critical Pathways; DNA Binding; DNA Methylation; DNA-Binding Proteins; Data; Development; Diabetes Mellitus; Dialysis procedure; Disease; Disease Progression; Embryonic Development; End stage renal failure; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Euchromatin; Expenditure; Failure; Family; Fibroblasts; Fibrosis; Funding; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Genome; Growth; Health Expenditures; Heterochromatin; Histone H3; Histones; Hypertension; Impairment; Information Systems; Injury; Intervention; Ischemia; Kidney; Kidney Diseases; Knowledge; Lysine; Maintenance; Mediating; Medicare; Mesenchymal; Methods; Methyltransferase; Modeling; Modification; Molecular Genetics; Myofibroblast; Natural regeneration; Nephrons; Nephrotoxic; Nuclear Proteins; Obesity; Paracrine Communication; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Population; Progressive Disease; Proteins; Public Health; Recruitment Activity; Reperfusion Therapy; Repressor Proteins; Role; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Specific qualifier value; Specificity; Stem cells; Stimulus; Stromal Cells; Testing; Tissues; Transplantation; United States; cell type; cost; effective therapy; epigenetic memory; epigenetic profiling; epigenetic regulation; epigenome; experimental study; histone methylation; histone methyltransferase; imprint; injured; innovation; insight; intercellular communication; interstitial; interstitial cell; kidney cell; link protein; migration; mouse model; nephrogenesis; nephrotoxicity; novel; novel therapeutics; precursor cell; programs; renal epithelium; response; transcriptome

ABSTRACT Gene expression patterns define the differentiated state of cells and their physiological functions. During embryonic development, gene expression patterns are set, in part, by epigenetic modifications that compartmentalize the genome into active euchromatin and silent heterochromatin. These modifications include histone and DNA methylation, which imprint a unique cell-type specific pattern on the epigenome such that cellular fates and phenotypic stability are maintained. In diseased states, the normal pattern of gene expression is disturbed which can result in altered cellular function, growth deregulation, abnormal cell signaling, and cell death. This competitive renewal application proposes that epigenetic changes can underlie the alterations in gene expression patterns observed in both acute and chronic renal disease. In the previous funding period, 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. The PTIP protein interacts with a variety of DNA binding proteins to recruit an MLL3/4 histone H3K4 methyltransferase complex to chromatin. This Pax2/PTIP interaction can be inhibited by the repressor proteins of the Tle/Groucho family, which are expressed in more differentiated renal epithelial cells. The current application will address how epigenetic regulators impact the fate of renal epithelial cells and renal interstitial fibroblasts in both acute and chronic disease states. Preliminary data strongly suggests that epigenetic modifications are needed to reset the proper transcriptional program of a renal epithelial cell during regeneration after acute injury. Our first specific aim will address the need for epigenetic modifiers in promoting regeneration and maintaining renal epithelia after injury. The second aim will address changes in renal interstitial fibroblasts or stromal cells in response to acute or chronic injury. The expansion of fibroblasts and myofibroblasts is a common pathology observed in the kidney and other tissues in chronic, progressive diseases. Yet, in limited cases the fibrosis is reversible. The reversibility suggests some type of epigenetic memory that may be altered in the case of irreversible fibrotic disease. What are the differences in gene expression and epigenetic modifications between a myofibroblast that defines an irreversible, progressive disease state and one that can be reversible? The answers to this question will reveal potential novel pathways that control phenotypic stability, cell proliferation, and disease progression in a variety of abnormal states. Given the limited treatment options currently available for chronic renal disease, understanding the epigenetic level of control in the disease state is paramount for developing new therapeutic options.

抽象的 基因表达模式定义了细胞的分化状态及其生理学 功能。在胚胎发育过程中，基因表达模式部分是由 表观遗传修饰将基因组划分为活性常染色质和 沉默异染色质。这些修饰包括组蛋白和 DNA 甲基化， 它在表观基因组上留下了独特的细胞类型特异性模式，使得细胞 命运和表型稳定性得以维持。在疾病状态下，正常模式 基因表达受到干扰，可能导致细胞功能改变、生长 失调、细胞信号异常和细胞死亡。此次竞争性更新 申请提出表观遗传变化可能是基因改变的基础 在急性和慢性肾脏疾病中观察到的表达模式。在之前的 资助期间，PI 已将 Pax2 确定为肾脏中关键的 DNA 结合蛋白 上皮谱系。随后，实验室发现 PTIP 作为接头蛋白，将 Pax2 连接到 组蛋白甲基化复合物，在靶基因上印上积极的表观遗传标记。这 PTIP 蛋白与多种 DNA 结合蛋白相互作用以招募 MLL3/4 组蛋白 H3K4 甲基转移酶复合到染色质。 Pax2/PTIP 相互作用可以是 受到 Tle/Groucho 家族阻遏蛋白的抑制，该蛋白表达于 肾上皮细胞分化程度更高。当前的应用程序将解决如何 表观遗传调节因子影响肾上皮细胞和肾间质的命运 急性和慢性疾病状态下的成纤维细胞。初步数据强烈表明 需要表观遗传修饰来重置正确的转录程序 急性损伤后再生过程中的肾上皮细胞。我们的第一个具体目标是 解决表观遗传修饰剂在促进再生和维持方面的需求 肾上皮损伤后。第二个目标是解决肾间质的变化 成纤维细胞或基质细胞对急性或慢性损伤的反应。的扩展 成纤维细胞和肌成纤维细胞是在肾脏和其他器官中观察到的常见病理学 慢性进行性疾病中的组织。然而，在有限的情况下，纤维化是可逆的。 这种可逆性表明某种类型的表观遗传记忆可能会在 不可逆纤维化疾病的病例。基因表达和基因表达有什么区别 肌成纤维细胞之间的表观遗传修饰定义了不可逆的， 进行性疾病状态和可以逆转的状态？这个问题的答案 将揭示控制表型稳定性、细胞增殖的潜在新途径， 以及各种异常状态下的疾病进展。鉴于治疗有限 目前可用于慢性肾脏疾病的选择，了解表观遗传水平 控制疾病状态对于开发新的治疗方案至关重要。