Duchenne muscular dystrophy (DMD) is the most common, inherited, lethal disease of childhood. Despite its high frequency of occurrence and the extensive knowledge of the molecular genetics of DMD, the lifespan or quality of life of DMD children has not improved over that which existed before the mutant gene was discovered approximately 13 years ago. Recently, our laboratories have shown that the histologically discernible pathology of the muscles of mdx mice, the most widely used animal model of the disease, could be reduced by more than half through interventions that inhibit cytotoxic T lymphocytes (CTLs). This is the greatest systemic improvement in the pathology of dystrophic muscle attained by any intervention, and it indicates that important new avenues for approaching DMD therapeutics may exist. The general goal of the investigation proposed here is to obtain more specific information concerning the role of T Iymphocytes in the death of dystrophic muscle, so that more specific therapeutic interventions with applicability to humans can be developed in future work. This will be done by: 1) determining whether distinct populations of T lymphocytes function through independent mechanisms in the autoreactive killing of mdx muscle, 2) testing whether binding of costimulatory molecules that are involved in Tcell activation is important for activation of autoreactive Tcells in mdx mice, and whether simultaneous blockade of these molecules is maximally effective for treatment, 3) testing whether the blockade of costimulating molecu1es of Tcells in mdx mice is most effective at reducing muscle pathology when applied early in the disease process, and 4) testing whether treatment of utrophin deficient mdx mice through Tcell depletions or with blockers of Tcell costimulation is effective in reducing muscle pathology and extending lifespan. Collectively, these findings can provide the basis for design of immune interventions to reduce the pathology of dystrophin deficient muscle.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046911-02
Application #
6375322
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Lymn, Richard W
Project Start
2000-05-05
Project End
2005-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
2
Fiscal Year
2001
Total Cost
$296,820
Indirect Cost
Name
University of California Los Angeles
Department
Miscellaneous
Type
Schools of Arts and Sciences
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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