Role of Type I Interferons in a Self-Sustaining Murine Model of Myositis

I 型干扰素在肌炎自我维持小鼠模型中的作用

• 批准号: 7497909
• 负责人: THOMAS A GRIFFIN
• 金额: $ 18.96万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-14 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497909
• 关键词: Affect; Breeding; Chronic; Chronic Disease; Class; Condition; Connective Tissue Diseases; Dermatomyositis; Development; Disease; Goals; Histocompatibility Antigens Class I; Human; Idiopathic Inflammatory Myopathies; Immune; Inclusion Body Myositis; Inflammation; Injury; Interferon Type I; Interferons; MHC Class I Genes; Maintenance; Mediating; Mediator of activation protein; Modeling; Mus; Muscle; Muscle Cells; Muscle Fibers; Myositis; Nature; Production; Proteins; Role; Skeletal Muscle; System; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Week; Work; in vivo; mouse model; novel; protein folding; response; type I interferon receptor

DESCRIPTION (provided by applicant): Idiopathic inflammatory myopathies comprise a group of connective tissue diseases that include dermatomyositis, polymyositis, and inclusion body myositis. Each of these conditions is characterized by chronic skeletal muscle inflammation and muscle fiber damage. Demonstration of persistent excessive expression of MHC class I molecules and an associated unfolded protein response (UPR) in affected muscle fibers in each of these conditions suggests a common mechanism for chronic muscle fiber injury. A central pathogenic role for MHC class I is indicated by a mouse model, in which chronic myositis is induced by conditional expression of a transgenic MHC class I molecule, H-2Kb, specifically in skeletal muscle fibers, which typically express very little endogenous MHC class I. Transgenic H-2Kb expression overwhelms the protein folding system of muscle fibers and activates an UPR, which appears to mimic what occurs in human myositis. Remarkably, several weeks of transgenic H-2Kb expression is all that is needed to induce self-sustaining myositis that is driven by increased expression of endogenous MHC class I molecules in muscle fibers, which persists long after transgenic H-2Kb expression is suppressed. The mechanism for induction and maintenance of endogenous MHC class I expression is unclear, though we theorize that type I interferons are involved, since they are potent inducers of MHC class I expression, and there is evidence for type I interferon action in affected muscle tissue in both mouse and human myositis. Additionally, we have recently discovered that the UPR can strongly enhance expression of type I interferons, particularly in the context of concurrent innate immune activation. This finding suggests a novel connection between the MHC class I-induced UPR and MHC class I-inducing type I interferons that leads us to hypothesize that UPR-induced type I interferons are produced by affected skeletal muscle fibers and are critical mediators of sustained endogenous MHC class I expression in the murine model of myositis. We will test this hypothesis by characterizing type I interferon production in muscle cells and tissue in response to excessive MHC class I expression and UPR activation, and by determining the role of type I interferon action in the mouse model of myositis by assessing the impact of type I interferon receptor deficiency. Ultimately, elucidating the mechanism of chronic myositis in the mouse model should make important contributions to understanding the mechanism of chronic human myositis, and provide strong rationale for development of novel treatments for human myositis that disrupt the proposed self-sustaining cycle of chronic disease.

描述（由申请人提供）：特发性炎症性肌病包括一组结缔组织疾病，其中包括皮肌炎，多聚肌炎和纳入体肌炎。这些疾病中的每一个的特征是慢性骨骼肌炎症和肌肉纤维损伤。在每种情况下，在受影响的肌肉纤维中，MHC I类分子的持续过度表达和相关的展开蛋白反应（UPR）的证明表明，这表明了慢性肌肉纤维损伤的共同机制。 A central pathogenic role for MHC class I is indicated by a mouse model, in which chronic myositis is induced by conditional expression of a transgenic MHC class I molecule, H-2Kb, specifically in skeletal muscle fibers, which typically express very little endogenous MHC class I. Transgenic H-2Kb expression overwhelms the protein folding system of muscle fibers and activates an UPR, which appears to mimic what发生在人肌炎中。值得注意的是，几周的转基因H-2KB表达是诱导自抑制的肌炎所需要的，这是由于肌肉纤维中内源性MHC I类分子表达增加所致，在转基因H-2KB表达后很长一段时间被抑制了。尽管我们将I型干扰素涉及的理论化，因为它们是MHC I类表达的有效诱导剂，并且有证据表明，I型I型干扰素在小鼠和人肌炎的肌肉组织中，I型干扰素作用有证据表明，I型I型干扰素的诱导和维持的机制尚不清楚。此外，我们最近发现，UPR可以强烈增强I型干扰素的表达，尤其是在并发的先天免疫激活的背景下。这一发现表明，MHC I类诱导的UPR与I类I类干扰素之间存在新的联系，这使我们假设UPR诱导的I型I型干扰素是由受影响的骨骼肌纤维产生的，并且是由持续的内源性MHC类I表达肌炎的持续内源性I类表达的关键介体。我们将通过表征I型干扰素在肌肉细胞和组织中表征过度MHC I类表达和UPR激活以及通过评估I类肌炎小鼠模型中I型I型Interferon受体缺乏症的影响来检验该假设。最终，在小鼠模型中阐明慢性肌炎的机制应为理解慢性人肌炎的机制做出重要贡献，并为破坏人类肌炎的新治疗方法提供了强有力的理由，这破坏了慢性疾病的自我维持周期。