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）：特发性炎性肌病包括一组结缔组织疾病，包括皮肌炎、多发性肌炎和包涵体肌炎。这些病症中的每一种的特征在于慢性骨骼肌炎症和肌纤维损伤。在这些条件中的每一个中，受影响的肌纤维中MHC I类分子和相关的未折叠蛋白反应（UPR）的持续过度表达的证明表明慢性肌纤维损伤的共同机制。MHC I类的中心致病作用由小鼠模型表明，其中慢性肌炎由转基因MHC I类分子H-2Kb的条件表达诱导，特别是在骨骼肌纤维中，其通常表达非常少的内源性MHC I类。转基因H-2Kb的表达使肌肉纤维的蛋白质折叠系统重新定位，并激活UPR，这似乎模拟了人类肌炎中发生的情况。值得注意的是，几周的转基因H-2Kb表达是诱导自我维持肌炎所需的全部，所述自我维持肌炎是由肌纤维中内源性MHC I类分子的表达增加驱动的，其在转基因H-2Kb表达被抑制后持续很长时间。诱导和维持内源性MHC I类表达的机制尚不清楚，尽管我们推测I型干扰素参与其中，因为它们是MHC I类表达的有效诱导剂，并且有证据表明I型干扰素在小鼠和人肌炎中受影响的肌肉组织中起作用。此外，我们最近发现，UPR可以强烈增强I型干扰素的表达，特别是在并发先天免疫激活的情况下。这一发现表明一种新的连接之间的MHC I类诱导的UPR和MHC I类诱导的I型干扰素，使我们假设UPR诱导的I型干扰素产生的受影响的骨骼肌纤维和持续的内源性MHC I类表达的关键介质在小鼠模型肌炎。我们将测试这一假设的特点，I型干扰素的生产在肌肉细胞和组织中响应过度的MHC I类表达和UPR激活，并通过确定I型干扰素的作用，在小鼠模型肌炎通过评估I型干扰素受体缺乏的影响。最终，阐明小鼠模型中慢性肌炎的机制应该对理解慢性人类肌炎的机制做出重要贡献，并为开发新的人类肌炎治疗方法提供强有力的理论基础，这些方法可以破坏所提出的慢性疾病的自我维持周期。