Pathogenesis of autoimmune myositis: Role of MHC Class 1

自身免疫性肌炎的发病机制：MHC 1 类的作用

• 批准号: 7186420
• 负责人: KANNEBOYINA NAGARAJU
• 金额: $ 21.9万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7186420
• 关键词: I kappa B beta; MHC class I antigen; autoimmune disorder; cysteine endopeptidases; disease /disorder model; endoplasmic reticulum; enzyme activity; gene expression profiling; genetically modified animals; laboratory mouse; laser capture microdissection; molecular pathology; muscle contraction; muscle proteins; myofibrils; myositis; northern blottings; nuclear factor kappa beta; pathologic process; posttranslational modifications; proteomics; sarcoplasmic reticulum; serine threonine protein kinase; striated muscles; thapsigargin; western blottings

DESCRIPTION (provided by applicant): Specific therapies are not currently available for systemic autoimmune rheumatic diseases. Development of specific and effective therapies requires the definition of pathways important in the disease pathogcncsis. The MHC class 1 mouse model of myositis is a powerful tool to identify such pathways. The long term goals of this proposal are to define the molecular pathways responsible for the skeletal muscle damage and dysfunction in autoimmune myositis. The MHC class I transgenic mice develop several features of human autoimmune polymyositis including myositis-specific autoantibodies. Preliminary experiments showed that the absence of lymphocytes and macrophages only partially ameliorates muscle fiber damage and dysfunction suggesting that over-expression of MHC class I in myofibers also initiates a specific sequence of ceil autonomous (myofiber) pathways leading to muscle damage. Thus, in this model both immune cells and skeletal muscle cells appear to play a role in the manifestation of full blown autoimmune myositis. Therefore, we propose that skeletal muscle cell damage in MHC class I expressing muscle fibers can partly be induced by cytotoxic T lymphocytes and partly by perturbation of intracellular homeostasis (ER stress response). Our preliminary experiments clearly show that the ER stress response pathway is highly up-regulated in both human myositis and in the mouse model. Defining the contribution of mechanisms of ER stress response and NF-kB pathways in MHC class I-expressing fibers and their role in muscle fiber damage and dysfunction is a major priority of this proposal. This hypothesis is pursued by a) blocking critical members of ER stress response pathway and NF-kB pathways in vivo, and b) identifying novel immune and non-immune pathways mediating muscle fiber damage and dysfunction by gene and protein expression profiling. The proposed aims will not only define predominant mechanisms of muscle fiber damage and dysfunction in vivo in transgenic mice but will also potentially identify new targets for therapeutic intervention in human myositis.

描述（由申请人提供）：