Duchenne muscular dystrophy (DMD) is a lethal, muscle-wasting disorder that is caused by mutations in the dystrophin gene. Current treatment options for DMD patients target secondary disease processes such as inflammation that can accelerate disease progression. However, therapies that employ immuno- suppressants and anabolic steroids commonly result in undesirable side effects with chronic use. Therefore, studies aimed at understanding the cellular and molecular mechanisms that regulate interactions between muscle and the immune system are needed. The investigation we propose may contribute to the development of new therapeutic modalities that target inflammation with reduced side effects. The overall objective of the investigation proposed here is to use the mdx mouse model of DMD to identify complex interactions between immune and muscle cells in muscular dystrophy and the consequences of these interactions on myofiber injury and regeneration. We specifically aim to test the hypothesis that macrophages in 4 week old mdx muscle are predominantly classically-activated and lyse mdx myotubes by free radical-mediated mechanisms (aim 1). In addition, we aim to test the hypothesis that macrophages in regenerative mdx muscle are alternatively-activated and promote muscle cell proliferation and differentiation (aim 2). Lastly, we will test the hypothesis that perturbations in the expression of Th1 and Th2 cytokines in vivo can significantly affect the course of mdx muscle injury and repair in vivo (aim 3). Elucidating the mechanisms that regulate that above interactions may result in the advancement of treatments that specifically perturb cytolytic immune cell interactions with muscle. To determine the physiological relevance of these macrophage phenotypes in vivo we propose using various mouse models. We will study the role of Th1 and Th2 cytokines in regulating the course of mdx muscle injury and repair by genetically ablating IL-10 and IFNg, which differentially regulate macrophage function. Because the interpretation of in vivo studies may be complicated by the numerous physiological factors that regulate macrophage functions, we will use n vitro assays to test the ability of classically- and alternatively-activated macrophages to promote muscle cell death and regeneration. The findings of this investigation may shed light on the inflammation-mediated, pathophysiological mechanisms that regulate dystrophinopathy. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31AR054724-01
Application #
7231079
Study Section
Special Emphasis Panel (ZRG1-DIG-H (29))
Program Officer
Boyce, Amanda T
Project Start
2006-09-25
Project End
2010-08-31
Budget Start
2006-09-25
Budget End
2007-08-31
Support Year
1
Fiscal Year
2006
Total Cost
$29,588
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
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
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
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
Villalta, S Armando; Nguyen, Hal X; Deng, Bo et al. (2009) Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy. Hum Mol Genet 18:482-96
Wehling-Henricks, Michelle; Sokolow, Sophie; Lee, Jamie J et al. (2008) Major basic protein-1 promotes fibrosis of dystrophic muscle and attenuates the cellular immune response in muscular dystrophy. Hum Mol Genet 17:2280-92