Understanding the role of IFN-gamma and CIITA in skeletal muscle

了解 IFN-γ 和 CIITA 在骨骼肌中的作用

基本信息

批准号：
8958379
负责人：
Judith Kimberly Davie
金额：
$ 38.94万
依托单位：
SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8958379
关键词：
Address Affect Age Animals Biological Assay Cachexia Catalytic Domain Cessation of life Chronic Clinical Complex Data Development Disease Drug Design EZH2 gene Engineering Epigenetic Process Event Foundations Gene Expression Gene Expression Profile Gene Targeting Genes Goals Healed Health Histone H3 Human Indium Individual Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Injury Innovative Therapy Interferon Type II Interferons Interleukin-6 Knowledge Life Locomotion Lysine MHC class II transactivator protein Mediating Methylation Modification Molecular Mus Muscle Muscle function Muscular Dystrophies Myogenic Regulatory Factors Myogenin Myopathy Myositis Natural regeneration Patients Pattern Phase Play Polycomb Process Proteins Recruitment Activity Regulation Repression Role Signal Transduction Skeletal Muscle Staging Therapeutic Intervention Trauma Up-Regulation Withdrawal Work cytokine healing improved in vivo insight mdx mouse mouse model muscle regeneration myogenesis novel programs promoter public health relevance repaired response treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The objective of this study is to identify how the inflammatory cytokine, interferon gamma (IFN-, which is up regulated in response to muscle injury resulting from trauma or disease, modulates muscle function and repair. The repair of skeletal muscle is essential to human health and inefficient repair leads to a loss of locomotion and eventually, to death. The inflammatory response plays an important role in responding to injury and initiating skeletal muscle repair. IFN- plays both positive and negative roles in myogenesis and is required for efficient muscle regeneration in vivo. We have discovered that IFN- acts through the class II transactivator, CIITA, by repressing the expression or activity o myogenin, the Myogenic Regulatory Factor (MRF) required for myofiber formation. In our studies to understand the mechanism of CIITA repression, we have discovered that IFN-, through CIITA, acts to maintain the expression of the polycomb complex, PRC2, which is normally silenced during differentiation. CIITA recruits the PRC2 complex to repressed gene promoters and PRC2 represses gene expression by catalyzing the methylation of histone H3, lysine 27 (H3K27me3). We propose that transient expression of IFN-, through CIITA, modulates myogenesis and promotes muscle repair, but suggest that deregulation of this signaling contributes to muscle disease by altering the gene expression profile in myofibers subject to IFN- stimulation. In this proposal, we will determine how IFN- and CIITA repress myogenin by determining if recruitment of activating factors such as MyoD are blocked in the presence of IFN-, defining the epigenetic modifications used in the repression and determining whether the PRC2 complex is required for repression. Next, we will determine if genes known to be altered in H3K27me3 patterns upon differentiation are methylated in response to IFN- and dependent on myogenin. These data will be correlated with the recruitment of EZH2 and the repression of gene expression. Lastly, we will confirm our findings in vivo and determine if chronic IFN- can inhibit muscle repair. This work will utilize a new mouse model engineered to express low chronic levels of IFN-. Using this mouse model, we will characterize the expression of CIITA and the PRC2 complex, determine if IFN- target genes are deregulated, and characterize repair in the presence of chronic IFN-. To understand the impact of IFN- as part of the inflammatory infiltrate, the methylation profile and gene expression of IFN- regulated gene targets will be assayed in mdx mice, which are known to have enhanced IFN- expression as part of a chronic inflammation response. The proposed work will strengthen our understanding of the molecular events that occur during inflammation in skeletal muscle. This information will not only help elucidate the normal process of repair and regeneration, but also extend our knowledge about the potential deleterious effects of chronic inflammation, enhancing the understanding of diseases such as muscular dystrophy, cachexia and inflammatory myopathies and allowing the development of innovative therapies for these diseases.

描述（由适用提供）：本研究的目的是确定炎症性细胞因子干扰素伽玛（IFN-如何受到因创伤或疾病而受到肌肉损伤的调节，调节肌肉功能和修复。骨骼肌肉的维修对人类健康和无效的疾病造成的损害至关重要，最终导致了损失的损失，最终造成了损失的损失。启动骨骼肌肉修复，在肌发生中起正面和负作用，并且在体内有效地再生，我们发现IFN-通过II类反式激活剂CIITA起作用。 IFN-通过CIITA可起作用，以维持Polycomb复合物的表达PRC2，该复合物通常在分化过程中被沉默。 CIITA通过催化组蛋白H3的甲基化，赖氨酸27（H3K27me3），将PRC2复合物募集到再现基因启动子和PRC2副本基因表达。我们提出，通过CIITA的IFN-的短暂表达调节肌发生并促进肌肉修复，但表明对这种信号传导的管制通过改变受IFN-刺激的肌外纤维中的基因表达谱来导致肌肉疾病。在该提案中，我们将通过确定在IFN-存在下募集激活因子（例如MYOD）是否会阻止诸如MYOD之类的激活因子，从而确定在表达中使用的表观遗传修饰并确定是否需要PRC2复合物，是否需要用于表达表达的表观遗传修饰。接下来，我们将确定在分化后H3K27me3模式中已知的基因是否会响应IFN-甲基化并依赖于肌蛋白。这些数据将与EZH2的募集和基因表达的表达相关。最后，我们将在体内确认我们的发现，并确定慢性IFN-是否可以抑制肌肉修复。这项工作将利用设计的新鼠标模型来表达慢性慢性IFN-。使用此小鼠模型，我们将表征CIITA和PRC2复合物的表达，确定IFN-靶基因是否受到管制，并在存在慢性IFN-的情况下进行修复。为了理解IFN-作为炎症性浸润的一部分的影响，将在MDX小鼠中分配IFN-调控基因靶靶标的甲基化谱和基因表达，已知它们已增强了IFN-表达，作为慢性炎症反应的一部分。提出的工作将加强我们对骨骼肌感染过程中发生的分子事件的理解。这些信息不仅将有助于阐明正常的修复和再生过程，还可以扩展我们对慢性感染潜在影响的知识，增强对诸如肌肉营养不良，卡氏症和炎症性肌病等疾病的理解，并允许对这些疾病的创新疗法发展。