Muscular dystrophies (MDs) are a broad group of inherited diseases that are characterized by progressive skeletal muscle weakness and wasting with a variable clinical course. The molecular mechanisms whereby individual skeletal muscle fibers undergo degeneration have not been well defined, and there are still no cures for these diseases. This proposal explores the therapeutic potential of mouse embryonic stem (ES) cells, with the ultimate goal of discovering principles that govern, the differentiation of ES cells into myogenic precursor cells that can be used in cell transplantation in murine models of MDs. To date, there has been no definitive demonstration that stem cells that arise in vitro during differentiation into embryoid bodies (EBs) are capable of engrafting either normal or dystrophic adult muscle. In collaboration with Cossu and colleagues, the Campbell laboratory showed that mesoangioblasts, stem cells isolated from embryonic dorsal aorta, can correct the phenotype in mouse model of MD. We are thus well positioned to investigate the nature of the common vascular-myogenic progenitor that can be formed in EBs, and the mechanisms governing the potential for such cells to engraft in adult myogenic microenvironments. We are proposing methods for isolating enriched populations of EB-derived progenitors using either selectable markers driven by myogenic specific promoters or cell purification via surface markers, and will endeavor to more carefully define the surface antigen phenotype and in vivo properties of this population of cells. We will test the hypotheses that engraftment is facilitated by homing, enhanced cell survival, or cell proliferation, and probe the molecular basis for these observations using a non-invasive bioluminescence monitoring system that will also allow us to investigate the long-term effect of cell-mediated therapy. Our results will enable methods for enhanced myogenic development from ES cells and reconstitution of the adult myogenic system as a model for myogenic research and cellular therapies. Future efforts will explore the similarities and differences in the myogenic potential of murine and human ES cells, and the therapeutic potential of in vitro differentiated human ES cells.
| Lee, Angela J; Buckingham, Edward T; Kauer, Aaron J et al. (2018) Descriptive Phenotype of Obsessive Compulsive Symptoms in Males With Duchenne Muscular Dystrophy. J Child Neurol 33:572-579 |
| González Coraspe, José Andrés; Weis, Joachim; Anderson, Mary E et al. (2018) Biochemical and pathological changes result from mutated Caveolin-3 in muscle. Skelet Muscle 8:28 |
| Martinez-Thompson, Jennifer M; Niu, Zhiyv; Tracy, Jennifer A et al. (2018) Autosomal dominant calpainopathy due to heterozygous CAPN3 C.643_663del21. Muscle Nerve 57:679-683 |
| Brun, Brianna N; Willer, Tobias; Darbro, Benjamin W et al. (2018) Uniparental disomy unveils a novel recessive mutation in POMT2. Neuromuscul Disord 28:592-596 |
| Larson, Austin A; Baker 2nd, Peter R; Milev, Miroslav P et al. (2018) TRAPPC11 and GOSR2 mutations associate with hypoglycosylation of ?-dystroglycan and muscular dystrophy. Skelet Muscle 8:17 |
| Carlson, Courtney R; Moore, Steven A; Mathews, Katherine D (2018) Dystrophinopathy muscle biopsies in the genetic testing ERA: One center's data. Muscle Nerve : |
| Wilson, Kristin; Faelan, Crystal; Patterson-Kane, Janet C et al. (2017) Duchenne and Becker Muscular Dystrophies: A Review of Animal Models, Clinical End Points, and Biomarker Quantification. Toxicol Pathol 45:961-976 |
| Dean, Marissa; Rashid, Salman; Kupsky, William et al. (2017) Child Neurology: LAMA2 muscular dystrophy without contractures. Neurology 88:e199-e203 |
| Shaw, Natalie D; Brand, Harrison; Kupchinsky, Zachary A et al. (2017) SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nat Genet 49:238-248 |
| Brun, Brianna N; Mockler, Shelley R H; Laubscher, Katie M et al. (2017) Childhood Activity on Progression in Limb Girdle Muscular Dystrophy 2I. J Child Neurol 32:204-209 |
Showing the most recent 10 out of 97 publications
