Role of DNA methylation in lupus

DNA 甲基化在狼疮中的作用

• 批准号: 10448446
• 负责人: Amr H Sawalha
• 金额: $ 46.99万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-25 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448446
• 关键词: Address; Adhesions; Animal Model; Attenuated; Bioinformatics; CD4 Positive T Lymphocytes; Cell Adhesion; Cell Adhesion Molecules; Chronic; DNA Methylation; Data; Disease; EZH2 gene; Epigenetic Process; Genes; Genetic; Genetic Transcription; Glucose; Glycolysis; Immune response; In Vitro; Inflammatory; Link; Lupus; Malignant Neoplasms; Mediating; MicroRNAs; Morbidity - disease rate; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Play; Research; Role; Signal Transduction; T cell response; T-Lymphocyte; Testing; Therapeutic; Transforming Growth Factor beta; Up-Regulation; cell motility; effector T cell; genetic approach; glucose metabolism; improved; in vivo; inhibitor; lupus prone mice; lupus-like; mortality; mouse model; new therapeutic target; novel; novel therapeutic intervention; overexpression; prevent; systemic autoimmune disease; targeted treatment; trend

Abstract Epigenetic dysregulation plays an important role in the pathogenesis of lupus. We recently described a pro-inflammatory epigenetic reprogramming of naïve CD4+ T cells upon increased disease activity in lupus patients. Our data suggest that the epigenetic regulator EZH2 might be mediating these epigenetic changes. Indeed, we show that EZH2 is increased in CD4+ T cells from lupus patients, and that both miR-26a and miR-101 which regulate EZH2 are downregulated. Both microRNAs have been shown to be sensitive to glucose concentrations, and we show that inhibiting glycolysis restores the expression of these two microRNAs in lupus CD4+ T cells. We hypothesize that increased glycolysis in lupus CD4+ T cells, results in upregulation of EZH2 via downregulating miR-26a and miR-101. Further, we provide evidence that EZH2 overexpression in lupus CD4+ T cells upregulates JAM-A which mediates increased T cell adhesion. We propose to determine a mechanistic explanation of EZH2 overexpression in lupus CD4+ T cells and how this might be linked to increased glycolysis and mTORC1 signaling. We will also identify the complete repertoire of genes and pathways dysregulated by EZH2 overexpression in lupus CD4+ T cells to identify novel therapeutic targets. In addition, given our data suggesting abrogation of increased CD4+ T cells adhesion in lupus patients following EZH2 inhibition in vitro, and that EZH2 inhibition in vivo significantly improves survival and ameliorates lupus-like disease in MRL/lpr lupus-prone mice, we propose to use genetic approaches to characterize the effects of targeted CD4+ T cell Ezh2 deletion in a murine model of lupus. EZH2 inhibitors are currently being trialed for a number of malignancies, and therefore, our results will pave the way for targeting EZH2, or EZH2-regulated genes we will identify, in lupus patients.

抽象的 表观遗传失调在狼疮的发病机制中起着重要作用。我们 最近描述了幼稚 CD4+ T 细胞的促炎症表观遗传重编程 狼疮患者的疾病活动增加。我们的数据表明表观遗传调节因子 EZH2 可能正在介导这些表观遗传变化。事实上，我们表明 EZH2 在 来自狼疮患者的 CD4+ T 细胞，调节 EZH2 的 miR-26a 和 miR-101 下调。两种 microRNA 均已被证明对葡萄糖浓度敏感， 我们发现抑制糖酵解可以恢复狼疮中这两种 microRNA 的表达 CD4+ T 细胞。我们假设狼疮 CD4+ T 细胞糖酵解增加，导致 通过下调 miR-26a 和 miR-101 上调 EZH2。进一步，我们提供证据 狼疮 CD4+ T 细胞中 EZH2 过度表达上调 JAM-A，从而介导增加 T细胞粘附。我们建议确定 EZH2 过度表达的机制解释 狼疮 CD4+ T 细胞及其与糖酵解和 mTORC1 增加的关系 发信号。我们还将确定基因和通路失调的完整库。 EZH2 在狼疮 CD4+ T 细胞中过度表达，以确定新的治疗靶点。此外， 鉴于我们的数据表明狼疮患者中增加的 CD4+ T 细胞粘附被消除 体外抑制 EZH2 后，体内抑制 EZH2 显着提高生存率 并改善 MRL/lpr 狼疮易感小鼠的狼疮样疾病，我们建议使用遗传 在小鼠模型中表征靶向 CD4+ T 细胞 Ezh2 缺失的影响的方法 狼疮。 EZH2 抑制剂目前正在针对多种恶性肿瘤进行试验，因此， 我们的结果将为靶向 EZH2 或我们将确定的 EZH2 调节基因铺平道路 狼疮患者。