The long-term goal of this proposal is to transition to an independent research career by defining disease mechanisms in autoimmune inflammatory myopathies (AIM), with a view to improving the diagnosis and treatment of these disorders. These diseases, which include dermatomyositis (DM) and polymyositis (PM), are characterized by muscle weakness, muscle inflammation, and autoantibodies. The mechanisms underlying AIM are poorly understood, and available therapies have deleterious side-effects and do not induce permanent remission. Defining disease mechanisms may allow development of specific and effective therapies.
In AIM, specific autoantibodies are strongly associated with distinct clinical phenotypes. The presence of anti-Mi-2 autoantibodies exclusively in patients with DM is a prominent example and understanding the basis of this association may shed light on underlying disease mechanisms. Recent data show low levels of myositis autoantigens (including Mi-2, a chromatin remodeling enzyme) in normal muscle. In contrast, myositis muscle has high myositis autoantigen levels, with enhanced expression particularly in regenerating cells. Interestingly, Mi-2 expression is only increased in DM and not PM muscle. Preliminary data from an in vitro myoblast differentiation system show that high Mi-2 levels in proliferating myoblasts are down-regulated during differentiation. Importantly, Mi-2 silencing with siRNA accelerated myoblast differentiation. Thus, we propose that Mi-2 may have a central role in myogenesis by inhibiting myoblast differentiation.
In Aim 1, we will use this in vitro system to determine the effects of Mi-2 sjlencing and over- expression on myoblast proliferation and differentiation, muscle regulatory factor expression, and myotube formation.
In Aim 2, we will use chromatin immunoprecipitation assays to identify candidate muscle-specific gene promoters that bind Mi-2. To broadly characterize the role of Mi-2 in regulating chromatin structure during myogenesis, we will perform large-scale ChlPSeq assays to define the entire Mi-2-DNA interactome in myoblasts and myotubes. Based on our understanding of Mi-2, its role in muscle differentiation, and its down-stream targets, we will undertake a detailed analysis of human muscle biopsy specimens in Aim 3. By defining normal and dysregulated muscle regeneration patterns in myositis and other muscle diseases, we hope to elucidate pathologic mechanisms and develop novel diagnostic tools.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR054783-05
Application #
8271311
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Boyce, Amanda T
Project Start
2008-06-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$129,330
Indirect Cost
$9,580
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Mohassel, Payam; Rosen, Paul; Casciola-Rosen, Livia et al. (2015) Expression of the dermatomyositis autoantigen transcription intermediary factor 1γ in regenerating muscle. Arthritis Rheumatol 67:266-72
Paik, Julie J; Corse, Andrea M; Mammen, Andrew L (2014) The co-existence of myasthenia gravis in patients with myositis: a case series. Semin Arthritis Rheum 43:792-6
Fiorentino, David F; Chung, Lorinda S; Christopher-Stine, Lisa et al. (2013) Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1γ. Arthritis Rheum 65:2954-62
Mohassel, Payam; Mammen, Andrew L (2013) Statin-associated autoimmune myopathy and anti-HMGCR autoantibodies. Muscle Nerve 48:477-83
Mohassel, Payam; Mammen, Andrew L (2013) The spectrum of statin myopathy. Curr Opin Rheumatol 25:747-52
Casciola-Rosen, Livia; Mammen, Andrew L (2012) Myositis autoantibodies. Curr Opin Rheumatol 24:602-8
Mammen, Andrew L; Pak, Katherine; Williams, Emma K et al. (2012) Rarity of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies in statin users, including those with self-limited musculoskeletal side effects. Arthritis Care Res (Hoboken) 64:269-72
Werner, Jessie L; Christopher-Stine, Lisa; Ghazarian, Sharon R et al. (2012) Antibody levels correlate with creatine kinase levels and strength in anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Rheum 64:4087-93
Casciola-Rosen, Livia; Hall, John C; Mammen, Andrew L et al. (2012) Isolated elevation of aldolase in the serum of myositis patients: a potential biomarker of damaged early regenerating muscle cells. Clin Exp Rheumatol 30:548-53
Mammen, Andrew L; Gaudet, Daniel; Brisson, Diane et al. (2012) Increased frequency of DRB1*11:01 in anti-hydroxymethylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Care Res (Hoboken) 64:1233-7

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