Virus induced genetic changes in the pathogenesis of autoimmune myositis

病毒诱导自身免疫性肌炎发病机制的遗传变化

• 批准号: 9226076
• 负责人: KANNEBOYINA NAGARAJU
• 金额: $ 19.97万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9226076
• 关键词: Affect; Apoptosis; Autoimmune Process; BCL-2 Protein; Bacteria; Biopsy; C57BL/6 Mouse; Calcium; Cell Death; Cell Death Signaling Process; Cells; Cessation of life; Chronic; Complex; Coxsackie B Viruses; DNA Methylation; Data Set; Dermatomyositis; Disease; Epigenetic Process; Etiology; Exposure to; Extravasation; Functional disorder; Gene Expression; Gene Expression Alteration; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genome; Genomics; HRK gene; Homeostasis; Human; Idiopathic Inflammatory Myopathies; Immune response; In Vitro; Inclusion Body Myositis; Individual; Infectious Agent; Infiltration; Inflammation; Inflammatory; Injury; Interferon Type I; Membrane; Mitochondria; Mononuclear; Mus; Muscle; Muscle Fatigue; Muscle Fibers; Muscle Weakness; Muscular Atrophy; Mutation; Myositis; Onset of illness; Parasites; Pathogenesis; Pathogenicity; Patients; Persons; Pharmaceutical Preparations; Polymyositis; Process; Protein Family; Role; Skeletal Muscle; Techniques; Testing; Tissues; Transgenic Mice; UV Radiation Exposure; Viral; Viral Genome; Virus; Virus Diseases; chronic autoimmune disease; disease phenotype; environmental agent; epigenome; experimental study; improved; in vivo; member; mitochondrial dysfunction; mouse model; muscle degeneration; repaired

Abstract: The etiology of idiopathic inflammatory myopathies is currently unknown. Temporal association of myositis onset with environmental agents such as viruses in certain individuals suggests that specific exposure, in the context of certain genetic backgrounds, can initiate muscle inflammation. Attempts to identify viruses in the tissues of IIM patients by sensitive techniques such as PCR have failed, bringing into question the viral etiology of these diseases and ruling out continual viral infection as a cause of the ongoing muscle inflammation in these patients. However, the previous studies do not exclude the possibility that viruses may alter the epigenome in affected cells and initiate pathogenic processes prior to their elimination by the host’s immune response, thus explaining the absence of viral genomes and presence of type I interferon signature gene expression in the myositis muscle tissue. Here we propose that it is unlikely that a unique environmental agent initiates the myositis disease phenotype, but it is highly likely that a diverse group of common environmental agents causes tissue specific epigenetic and gene expression alterations in cell homeostasis, survival and death genes, resulting in the manifestation of the disease phenotype in persons with a susceptible genetic background. There is also significant evidence that epigenetic changes at the genomic level could be responsible for the pathogenesis of complex inflammatory diseases of unknown etiology. In preliminary in vitro experiments, we found that Coxsackie B virus infection alters the DNA methylation and expression of genes controlling membrane and cytoskeletal stability, cell death and apoptosis. Here we hypothesize that sustained increased expression of HRK causes mitochondrial dysfunction that compromises sarcolemmal integrity, leading to increased cytosolic calcium, membrane leakiness, cell death and inflammation, which enhance muscle degeneration and wasting in myositis. Aim 1:To test whether changes in the expression of HRK alter membrane repair and cell death signaling in vitro in human skeletal muscle, Aim 2:To determine whether decreased expression of HRK in skeletal muscle improves muscle damage and weakness in myositis-prone mice and Aim 3:To determine whether increased expression of HRK in skeletal muscle induces muscle damage and weakness in myositis prone and wild-type (C57BL/6) mice. The proposed studies will help elucidate the genetic basis for the disease phenotype, and their results may radically change our current concepts on the role common environmental agents in initiating and sustaining chronic autoimmune diseases such as myositis.

摘要： 特发性炎性肌病的病因目前尚不清楚。肌炎的时间相关性 在某些个体中，与环境因子（如病毒）的接触表明， 在某些遗传背景下，可以引发肌肉炎症。试图在病毒中识别病毒， 通过敏感技术如PCR检测IIM患者的组织失败，这引起了对病毒病因学的质疑。 这些疾病，并排除了持续的病毒感染作为持续的肌肉炎症的原因， 这些病人。然而，先前的研究并不排除病毒可能改变 表观基因组在受影响的细胞和启动致病过程之前，他们消除宿主的免疫 应答，从而解释了病毒基因组的缺失和I型干扰素特征基因的存在 在肌炎肌肉组织中的表达。在这里，我们提出，一个独特的环境因素不太可能 启动肌炎疾病表型，但很可能是一个不同的群体，共同的环境 药物引起细胞稳态、存活和分化中的组织特异性表观遗传和基因表达改变。 死亡基因，导致疾病表型在具有易感基因的人中表现出来。 背景还有重要的证据表明，基因组水平的表观遗传变化可能是 负责病因不明的复杂炎性疾病的发病机制。初步体外 实验中，我们发现科萨基B病毒感染改变了DNA甲基化和基因表达 控制膜和细胞骨架的稳定性、细胞死亡和凋亡。在这里，我们假设， HRK表达的增加导致线粒体功能障碍从而损害肌膜完整性， 导致细胞溶质钙增加、膜渗漏、细胞死亡和炎症， 肌炎中的肌肉变性和萎缩。目的1：检测HRK表达的变化是否改变了 目的2：在体外研究人骨骼肌的膜修复和细胞死亡信号， 骨骼肌中HRK表达减少可改善肌炎倾向患者的肌肉损伤和无力 目的3：为了确定骨骼肌中HRK表达的增加是否会诱导肌肉 损伤和虚弱。拟议的研究将有助于 阐明疾病表型的遗传基础，他们的结果可能会从根本上改变我们目前的 关于常见环境因子在引发和维持慢性自身免疫性疾病中的作用的概念 例如肌炎。