Duchenne Muscular Dystrophy (DMD) is a progressive disorder in which the absence of the dystrophin protein results in loss of the dystrophin bridge at the muscle membrane. Recent work demonstrates the involvement of dystrophin in blood flow regulation, which is disturbed in DMD and causes increased muscle damage. However, the importance of angiogenesis in DMD treatment has not yet been well addressed. We propose that administration of pro-angiogenic factors can restore muscle fibers and blood vessels. To reveal the relationship between neuromuscular disease and angiogenesis, we recently created Flt-1 heterozygous mdx mice (mdx:Flt- 1+/-). mdx mice serve as a model for DMD, and vascular endothelial growth factor (VEGF) binds with Flt-1 receptors to negatively regulate angiogenesis. Recently, our work revealed that the mdx:Flt-1+/- mice display an increased number of blood vessels in addition to improved muscle pathology and function (Verma et al., 2010). Utrophin deficient mdx mice (mdx:utrn-/-) display a more severe phenotype than mdx mice, and the mdx:utrn-/- mice more closely resemble a human DMD phenotype. Importantly, mdx:utrn-/-:Flt-1+/- triple mutant mice display improved muscle histology and significantly higher survival rates compared to mdx:utrn-/-:Flt-1+/+ mice. Our project will build on these preliminary data to more closely reveal how increased angiogenesis ultimately affects the DMD phenotype in mdx mice. In addition, we will examine whether increased vasculature provided by the administration of an anti-Flt-1 peptide or shRNA for Flt-1 that block Flt-1 function can improve the muscular dystrophic phenotype in mdx and mdx:utrn-/- mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR061545-03
Application #
8729809
Study Section
Special Emphasis Panel (ZAR1-EHB (M1))
Program Officer
Nuckolls, Glen H
Project Start
2012-08-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
$73,990
Indirect Cost
$24,990
Name
University of Minnesota Twin Cities
Department
Neurology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Motohashi, Norio; Asakura, Yoko; Asakura, Atsushi (2014) Isolation, culture, and transplantation of muscle satellite cells. J Vis Exp :
Shimizu-Motohashi, Yuko; Asakura, Atsushi (2014) Angiogenesis as a novel therapeutic strategy for Duchenne muscular dystrophy through decreased ischemia and increased satellite cells. Front Physiol 5:50
Ennen, James P; Verma, Mayank; Asakura, Atsushi (2013) Vascular-targeted therapies for Duchenne muscular dystrophy. Skelet Muscle 3:9