Disease chronicity in juvenile dermatomyositis (JDM): Epigenetic clues

青少年皮肌炎 (JDM) 的慢性疾病：表观遗传线索

• 批准号: 8074774
• 负责人: LAUREN M. PACHMAN
• 金额: $ 47.63万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-29 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074774
• 关键词: Disease; chronicity; juvenile; dermatomyositis; JDM

DESCRIPTION (provided by applicant): Juvenile dermatomyositis (JDM) is the most common pediatric inflammatory myopathy and occurs in young children (mean age at onset of symptoms, 6.7 years; girl: boy ratio=2.3:1) with 1-2% mortality and increased morbidity secondary to dystrophic calcifications and secondary contractures. The children have a decreased quality of life, but the role of chronic inflammation has not been evaluated. The duration of time of the untreated inflammation is a critical factor: untreated symptoms of greater than two months are associated with a chronic rash and upregulation of vascular remodeling genes on gene expression profile studies. The chronic rash is also associated with loss of nailfold capillary end row loops, impaired absorption of medications, and as young adults, the patients appear prone to premature cardiovascular damage. Damage to endothelial cells is mediated by IFN- 1 and TNF-1, and both cytokines are increased in JDM sera and tissue. Increased TNF-1 levels are associated with a polymorphism in the promoter region of TNF-1-308. We also found a complex gene-gene-gender interaction between the OPN and TNF-1 promoter regions in JDM children. This defined a high serum IFN-1 subgroup within JDM, which may contribute to the increased incidence of JDM in girls. In treating JDM, the accepted guide to therapy is serum levels of muscle enzymes, which normalize rapidly, leaving a void. A major barrier to providing effective therapy in JDM is the lack of biomarkers of inflammation as well as prognostic indicators of disease severity. The purpose of this study is to identify epigenetic mechanisms - differences in global methylation and miRNA expression - critical in dissecting the impact of chronic inflammation and gender on JDM microvasculopathy. We hypothesize: 1) Decreased quality of life in chronic JDM is related less to weakness than to the chronic skin involvement, associated with long untreated disease, and, 2) identification of epigenetic regulatory mechanisms and specific miRNAs in JDM muscle and in endothelial precursor cells (EPCs) will disclose novel pathogenetic mechanisms that will guide the development of more effective therapy. To accomplish this goal, well-characterized muscle biopsies from untreated children with JDM will be compared: 1) short duration (< 2 month) vs. long (e 2 months) duration, and 2) age-matched boys compared with girls, also matched for disease duration. In Specific Aim 1, global methylation studies, comparing JDM with controls will identify areas of hypomethylation, such as the WT1 and HOX genes, and test their relation to intensity levels of miRNA expression. Specific Aim 2 will determine the association of levels of miRNA expression with the child's quality of life, disease activity scores (DAS), and their TNF-1-308 AA/AG vs GG status. For example, we found that miR-34a, upregulated in JDM GG with short disease duration modulates the expression of the transcriptional activator Bcl12, important in the apoptotic pathway. In Specific Aim 3, endothelial precursor cells (EPCs) will be isolated from the blood of JDM and age-gender matched controls and their epigenetic features characterized. In addition, their function will be studied in vitro and compared with the extent of the child's structural loss of nailfold capillary end row loops. The isolated EPCs will then be tested in gain/loss of function experiments, with the goal of restoration of normality. It is anticipated that the scientific knowledge gained from the proposed work will inform our future decision making and lead to more rational and effective interventions. PUBLIC HEALTH RELEVANCE: Juvenile dermatomyositis (JDM) is an autoimmune disease of children, in which there is damage to the small blood vessels; chronic inflammation is associated with persistent rash, loss of range of motion, deposits of calcifications and even the ability to perform tasks like climbing stairs or lifting objects and, therefore, affects the child's quality of life. In this study, the quality of life of the children with JDM will be determined and correlated with their epigenetic status - inherited changes in phenotype (individual's observable traits) determined by genes and the environment - by testing diagnostic muscle biopsies from untreated children with JDM with long (>2 months) compared with short disease duration (d 2 months) and boys compared with girls (matched for disease duration) and age-, gender-matched healthy controls. The goal is to identify specific markers, like microRNA, or "turned on genes" that may be key to repair the vascular damage and to identify more effective medical interventions.

描述（由申请人提供）：少年皮肌炎（JDM）是最常见的小儿炎症性肌病，发生在幼儿中（症状的平均年龄为6.7岁；女孩：男孩比率= 2.3：1），死亡率为1-2％，死亡率和次要症状性疾病疾病的发病率增加。儿童的生活质量降低，但尚未评估慢性炎症的作用。未经治疗的炎症的持续时间是关键因素：在基因表达谱研究中，未治疗的症状大于两个月的慢性皮疹和血管重塑基因的上调有关。慢性皮疹还与指甲毛细管终端环的丧失，药物吸收受损以及年轻人一样，患者似乎容易发生过早的心血管损伤。内皮细胞的损伤是由IFN-1和TNF-1介导的，JDM血清和组织中的两种细胞因子都增加了。 TNF-1水平升高与TNF-1-308启动子区域的多态性有关。我们还发现JDM儿童中OPN和TNF-1启动子区域之间的基因基因性别相互作用。这定义了JDM内的高血清IFN-1亚组，这可能导致女孩在女孩中的发病率增加。在治疗JDM时，接受的治疗指南是肌肉酶的血清水平，它们迅速归一化，留下空隙。在JDM中提供有效治疗的主要障碍是缺乏炎症的生物标志物以及疾病严重程度的预后指标。这项研究的目的是鉴定表观遗传机制 - 全球甲基化和miRNA表达的差异 - 至关重要地解剖慢性炎症和性别对JDM微瘤病的影响。我们假设：1）慢性JDM的生活质量降低与弱点相比，与慢性皮肤受累相比，与长期未经治疗的疾病有关，以及2）鉴定表观遗传调节机制和JDM肌肉中的特定miRNA，在JDM肌肉中和内皮前体细胞（EPCS）（EPCS）将透露新型的经济学疗法，以提供更多的发展，从而有效地进行了更多的发展。为了实现这一目标，将比较来自未经治疗的JDM儿童的特征良好的肌肉活检：1）与女孩相比，与女生相比，持续时间短（<2个月）与长期（E 2个月）的持续时间（E 2个月）和2个年龄匹配的男孩，疾病持续时间也匹配。在特定的目标1中，将JDM与对照组进行比较的全球甲基化研究将确定诸如WT1和HOX基因等甲基化的区域，并测试其与miRNA表达强度水平的关系。具体目标2将确定miRNA表达水平与孩子的生活质量，疾病活动评分（DAS）及其TNF-1-308 AA/AG与GG状态的关联。例如，我们发现在JDM GG中上调的miR-34a具有较短的疾病持续时间，调节了转录激活剂BCl12的表达，在凋亡途径中很重要。在特定的目标3中，将从JDM的血液和年龄匹配的对照及其表观遗传特征中分离出内皮前体细胞（EPC）。此外，将在体外研究其功能，并将其与儿童指甲毛细管终端环的结构损失程度进行比较。然后将在功能实验的增益/丧失实验中测试孤立的EPC，以恢复正态性。预计从拟议的工作中获得的科学知识将为我们未来的决策提供信息，并导致更理性和有效的干预措施。 公共卫生相关性：少年皮肌炎（JDM）是一种儿童的自身免疫性疾病，其中小血管受到损害；慢性炎症与持续的皮疹，运动范围丧失，钙化沉积以及执行诸如爬楼楼梯或提升物体之类的任务的能力有关，因此会影响孩子的生活质量。 In this study, the quality of life of the children with JDM will be determined and correlated with their epigenetic status - inherited changes in phenotype (individual's observable traits) determined by genes and the environment - by testing diagnostic muscle biopsies from untreated children with JDM with long (>2 months) compared with short disease duration (d 2 months) and boys compared with girls (matched for disease duration) and age-, gender-matched healthy控件。目的是识别特定的标记，例如microRNA或“打开基因”，这可能是修复血管损伤并确定更有效的医疗干预措施的关键。