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: 8152223
• 负责人: LAUREN M. PACHMAN
• 金额: $ 45.58万
• 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/8152223
• 关键词: Adult; Affect; Age; Alleles; Apoptotic; Area; Articular Range of Motion; Autoimmune Diseases; Autoimmune Process; Biological Markers; Biopsy; Blood; Blood Vessels; Blood capillaries; Cardiovascular system; Cell Cycle Kinetics; Cell physiology; Characteristics; Child; Childhood; Chronic; Chronic Disease; Complex; Contracture; DNA; DNA Methylation; Data; Decision Making; Deposition; Dermatomyositis; Development; Diagnostic; Diagnostic tests; Disease; Dystrophic Calcification; Endothelial Cells; Environment; Enzymes; Epigenetic Process; Estradiol; Exanthema; Face; Female; Functional disorder; Future; Gender; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Family; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Status; Genetic Transcription; Goals; Histones; Homeobox Genes; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Inherited; Interferons; Intervention; Joints; Knowledge; Lead; Left; Lifting; Link; Mediating; Medical; Methylation; MicroRNAs; Modeling; Modification; Molecular; Molecular Profiling; Morbidity - disease rate; Muscle; Myopathy; Myositis; Normalcy; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Process; Production; Promoter Regions; Quality of life; Race; Role; Scleroderma; Secondary to; Serum; Severity of illness; Skin; Subgroup; Symptoms; Systemic Lupus Erythematosus; TNF gene; Testing; Time; Tissue-Specific Gene Expression; Tissues; Transcription Coactivator; Tube; Up-Regulation; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Vascular remodeling; WT1 gene; Work; absorption; bisulfite; boys; calcification; capillary; cytokine; effective intervention; effective therapy; girls; illness length; loss of function; mortality; novel; osteopontin; outcome forecast; precursor cell; premature; prognostic indicator; promoter; public health relevance; repaired; research study; restoration; trait; young adult

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）：青少年皮肌炎 (JDM) 是最常见的儿科炎症性肌病，发生于幼儿（症状出现的平均年龄为 6.7 岁；女孩：男孩比例=2.3:1），死亡率为 1-2%继发于营养不良性钙化和继发性挛缩的发病率增加。儿童的生活质量下降，但慢性炎症的作用尚未得到评估。未经治疗的炎症的持续时间是一个关键因素：超过两个月的未经治疗的症状与慢性皮疹和基因表达谱研究中血管重塑基因的上调有关。慢性皮疹还与甲襞毛细血管末端行环的丧失、药物吸收受损有关，并且作为年轻成人，患者似乎容易过早出现心血管损伤。对内皮细胞的损伤是由 IFN-1 和 TNF-1 介导的，两种细胞因子在 JDM 血清和组织中都会增加。 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 儿童的 OPN 和 TNF-1 启动子区域之间存在复杂的基因-基因-性别相互作用。这定义了 JDM 中的高血清 IFN-1 亚组，这可能导致女孩 JDM 发病率增加。在治疗 JDM 时，公认的治疗指南是血清肌酶水平，该水平迅速恢复正常，留下空白。为 JDM 提供有效治疗的一个主要障碍是缺乏炎症生物标志物以及疾病严重程度的预后指标。本研究的目的是确定表观遗传机制（整体甲基化和 miRNA 表达的差异），这对于剖析慢性炎症和性别对 JDM 微血管病变的影响至关重要。我们假设：1) 慢性 JDM 的生活质量下降与虚弱的关系较小，而与慢性皮肤受累有关，而慢性皮肤受累与长期未经治疗的疾病有关，2) 在 JDM 肌肉和内皮前体细胞中鉴定表观遗传调节机制和特定 miRNA （EPC）将揭示新的发病机制，这将指导更有效疗法的开发。为了实现这一目标，将对未经治疗的 JDM 儿童的特征明确的肌肉活检进行比较：1) 短持续时间（< 2 个月）与长持续时间（e 2 个月），以及 2) 年龄匹配的男孩与女孩的比较，与病程相匹配。在具体目标 1（全局甲基化研究）中，将 JDM 与对照进行比较将识别低甲基化区域，例如 WT1 和 HOX 基因，并测试它们与 miRNA 表达强度水平的关系。具体目标 2 将确定 miRNA 表达水平与儿童的生活质量、疾病活动评分 (DAS) 及其 TNF-1-308 AA/AG 与 GG 状态之间的关联。例如，我们发现在病程较短的 JDM GG 中上调的 miR-34a 可调节转录激活剂 Bcl12 的表达，而 Bcl12 在细胞凋亡途径中很重要。在具体目标 3 中，将从 JDM 和年龄性别匹配对照的血液中分离出内皮前体细胞 (EPC)，并表征其表观遗传特征。此外，还将在体外研究它们的功能，并与儿童甲襞毛细血管端行环结构损失的程度进行比较。然后，分离的 EPC 将在功能获得/丧失实验中进行测试，目的是恢复正常。预计从拟议工作中获得的科学知识将为我们未来的决策提供信息，并导致更合理和有效的干预措施。 公共卫生相关性：青少年皮肌炎 (JDM) 是一种儿童自身免疫性疾病，会损害小血管；慢性炎症与持续性皮疹、活动范围丧失、钙化沉积，甚至无法执行爬楼梯或举起物体等任务有关，因此会影响儿童的生活质量。在这项研究中，JDM 儿童的生活质量将被确定，并与他们的表观遗传状态相关联 - 由基因和环境决定的表型遗传变化（个体的可观察特征） - 通过测试未经治疗的 JDM 儿童的诊断性肌肉活检长病程（> 2 个月）与短病程（d 2 个月）相比，男孩与女孩（病程匹配）以及年龄、性别匹配的健康对照。目标是识别特定标记，如 microRNA 或“开启基因”，它们可能是修复血管损伤和确定更有效的医疗干预措施的关键。