Duchenne muscular dystrophy (DMD) is one of the most common genetic diseases affecting 1 in 3,500 male births. It is characterized by progressive muscle weakness and premature death from cardiac and respiratory failure. It is caused by a defective dystrophin gene on the X chromosome that results in , myofiber degeneration, necrosis, regeneration, and remarkable secondary inflammation and fibrosis. Although gene or cell replacement may provide ultimate cure, these approaches are currently not feasible. Therefore modifying secondary pathogenesis, inflammation and fibrosis, may provide an important alternative approach to halt disease progression. Transforming growth factor-beta 1 (TGF-B1), a widely expressed multifunctional cytokine, has been demonstrated to be a critical regulator for cell growth and differentiation, inflammation, and fibrosis. It has been shown that the level of TGF-B1 expression is upregulated and appears to correlate with fibrosis in DMD muscle biopsies. Blocking TGF- B1 function can reduce collagen I mRNA expression in the diaphragm of mdx mice, a mouse model of DMD. This study proposes to use in vivo loss-of-function and gain-of-function approaches to test our central hypothesis that TGF-B1 plays an important role in regulating inflammation and fibrosis in dystrophin deficient mice, mdx and dko mice. We propose four specific aims:
Specific aim 1 will determine the correlation of expression of TGF-B1, 2, 3 and their receptors (I, II, III) with inflammation and fibrosis in diaphragm and hind limb muscles in mdx and dko mice.
Specific aim 2 will determine the impact of blocking TGF-B1 function on mdx diaphragm fibrosis.
Specific aim 3 will determine the impact of loss of TGF-B1 expression on diaphragm fibrosis in immune-deficient mdx mice.
Specific aim 4 will determine the impact of overexpression of TGF-B1 on disease progression and survival of dko mice. The proposed studies will provide us with a better understanding of the dynamic roles that TGF-B1 plays in vivo in the muscle inflammation and fibrosis associated with dystrophin deficiency. Knowledge gained from these studies may lead to development of a novel therapeutic approach that targets TGF-B1 expression to ameliorate inflammation and fibrosis in patients with DMD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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NST-2 Subcommittee (NST)
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Chen, Daofen
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Cleveland Clinic Lerner
Internal Medicine/Medicine
Schools of Medicine
United States
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