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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
7R01AR050478-02
Application #
7186420
Study Section
Special Emphasis Panel (ZRG1-MOSS-D (04))
Program Officer
Gretz, Elizabeth
Project Start
2005-04-01
Project End
2010-01-31
Budget Start
2005-11-01
Budget End
2006-01-31
Support Year
2
Fiscal Year
2005
Total Cost
$218,951
Indirect Cost
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
Nagaraju, Kanneboyina; Ghimbovschi, Svetlana; Rayavarapu, Sree et al. (2016) Muscle myeloid type I interferon gene expression may predict therapeutic responses to rituximab in myositis patients. Rheumatology (Oxford) 55:1673-80
Kornegay, Joe N; Spurney, Christopher F; Nghiem, Peter P et al. (2014) Pharmacologic management of Duchenne muscular dystrophy: target identification and preclinical trials. ILAR J 55:119-49
Henriques-Pons, Andrea; Yu, Qing; Rayavarapu, Sree et al. (2014) Role of Toll-like receptors in the pathogenesis of dystrophin-deficient skeletal and heart muscle. Hum Mol Genet 23:2604-17
Sali, Arpana; Many, Gina M; Gordish-Dressman, Heather et al. (2013) The proton pump inhibitor lansoprazole improves the skeletal phenotype in dystrophin deficient mdx mice. PLoS One 8:e66617
Rayavarapu, Sree; Coley, William; Cakir, Erdinc et al. (2013) Identification of disease specific pathways using in vivo SILAC proteomics in dystrophin deficient mdx mouse. Mol Cell Proteomics 12:1061-73
Takanohashi, Asako; Prust, Morgan; Wang, Jichuan et al. (2013) Elevation of proinflammatory cytokines in patients with Aicardi-Goutieres syndrome. Neurology 80:997-1002
Heier, Christopher R; Damsker, Jesse M; Yu, Qing et al. (2013) VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects. EMBO Mol Med 5:1569-85
Yu, Qing; Sali, Arpana; Van der Meulen, Jack et al. (2013) Omigapil treatment decreases fibrosis and improves respiratory rate in dy(2J) mouse model of congenital muscular dystrophy. PLoS One 8:e65468
Rayavarapu, Sree; Coley, William; Van der Meulen, Jack H et al. (2013) Activation of the ubiquitin proteasome pathway in a mouse model of inflammatory myopathy: a potential therapeutic target. Arthritis Rheum 65:3248-58
Huynh, Tony; Uaesoontrachoon, Kitipong; Quinn, James L et al. (2013) Selective modulation through the glucocorticoid receptor ameliorates muscle pathology in mdx mice. J Pathol 231:223-35

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