Duchenne muscular dystrophy (DMD) is the most common, inherited, lethal disease of childhood. Although mutations in the dystrophin gene are primarily responsible for DMD and animal models of DMD, many features of dystrophinopathies indicate that secondary processes can contribute substantially to pathology. Recent findings have indicated that the immune system can contribute significantly to the pathological progression of dystrophin-deficiency in the mdx mouse model of the disease. The long-term goal of our studies of the pathology of dystrophin-deficiency is to identify the specific immune cells and mechanisms that promote the pathology of dystrophin-deficiencies, after which we will use that information for the development of immune-based therapeutics. Although our preliminary data implicate both myeloid and lymphoid cells in promoting the dystrophic pathology, the studies proposed here will focus on cytotoxic mechanisms that are mediated by macrophages and eosinophils in dystrophic muscle. Our rationale for focusing on these specific myeloid cells is that our preliminary findings strongly implicate these cells in promoting the pathology of dystrophin-deficiency through both innate and acquired immune responses. Our general strategy will be to assess the effect on muscle pathology of depletion of specific myeloid cell populations from the dystrophic mdx mouse. In addition, the effect of those depletions on the lifespan of the dystrophic mdx/utrophin-deficient mice will be assessed because these mice die from muscular dystrophy at an early age. We will also test whether introducing null mutations of the inducible nitric oxide synthase gene or major basic protein gene into mdx mice will reduce muscle pathology, because our findings implicate cytotoxic pathways in the mdx pathology that involve the products of these genes. Results of the study proposed here will permit us to determine whether therapeutic approaches that are based on reducing myeloid cell mediated pathology can be productive approaches to the treatment of these forms of muscular dystrophy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047721-04
Application #
6786792
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Nuckolls, Glen H
Project Start
2001-09-24
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
4
Fiscal Year
2004
Total Cost
$423,254
Indirect Cost
Name
University of California Los Angeles
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Tidball, James G; Wehling-Henricks, Michelle (2014) Nitric oxide synthase deficiency and the pathophysiology of muscular dystrophy. J Physiol 592:4627-38
Tidball, James G; Bertoni, Carmen (2014) Purloined mechanisms of bacterial immunity can cure muscular dystrophy. Cell Metab 20:927-9
Villalta, S Armando; Rosenthal, Wendy; Martinez, Leonel et al. (2014) Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. Sci Transl Med 6:258ra142
Deng, Bo; Wehling-Henricks, Michelle; Villalta, S Armando et al. (2012) IL-10 triggers changes in macrophage phenotype that promote muscle growth and regeneration. J Immunol 189:3669-80
Wehling-Henricks, Michelle; Tidball, James G (2011) Neuronal nitric oxide synthase-rescue of dystrophin/utrophin double knockout mice does not require nNOS localization to the cell membrane. PLoS One 6:e25071
Villalta, S Armando; Deng, Bo; Rinaldi, Chiara et al. (2011) IFN-? promotes muscle damage in the mdx mouse model of Duchenne muscular dystrophy by suppressing M2 macrophage activation and inhibiting muscle cell proliferation. J Immunol 187:5419-28
Tidball, James G (2011) Mechanisms of muscle injury, repair, and regeneration. Compr Physiol 1:2029-62
Villalta, S Armando; Rinaldi, Chiara; Deng, Bo et al. (2011) Interleukin-10 reduces the pathology of mdx muscular dystrophy by deactivating M1 macrophages and modulating macrophage phenotype. Hum Mol Genet 20:790-805
Wehling-Henricks, Michelle; Jordan, Maria C; Gotoh, Tomomi et al. (2010) Arginine metabolism by macrophages promotes cardiac and muscle fibrosis in mdx muscular dystrophy. PLoS One 5:e10763
Tidball, James G; Villalta, S Armando (2010) Regulatory interactions between muscle and the immune system during muscle regeneration. Am J Physiol Regul Integr Comp Physiol 298:R1173-87

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