Congenital muscular dystrophy is often caused by deficiency in laminin a2 (merosin) expression in the basement membrane surrounding muscle fibers. Merosin-deficient congenital muscular dystrophy (MCMD) is characterized by severe muscle weakness shortly after birth that does not improve significantly enough to allow normal ambulatory motion. The dy mutant mouse lines also lack normal laminin u2 expression and provide an experimental models for this disease. Severe mutants such as the dyw strain undergo muscle fiber degeneration followed by regeneration, but these fibers die in a process involving apoptosis. Ultimately mice die within 4 months of age. We have found that muscle specific overexpression of Bcl-2 (an inhibitor of apoptosis) can significantly prolong the survival dyw mice and improve post-weaning growth thus indicating that regulation of the cell death specifically in muscle cells has a dramatic effect on this disease progression. Additionally, we find that d/v animals deficient in Bax, a related pro-apoptotic protein, exhibit even greater longevity and growth along with reduced hind limb paralysis associated with laminin a2- deficient myelination defects. Experiments are proposed to further explore the role of Bcl-2 and Bax in the progression of laminin a2-deficient muscle pathology and determine their effects on apoptosis, regeneration and survival at both early and later stages of disease. We will also examine expression of other apoptotic regulatory molecules, specifically FLIPL, ARC, XIAP, and Apaf-1, in normal and laminin a2-deficient muscle cells. Expression of these proteins will be experimentally altered in vivo to determine whether or not they can regulate the survival of laminin u2-deficient muscle and if disease progression can be modulated at different stages by altering their levels. These results will further our understanding of mechanisms controlling the apoptotic process during laminin a2-deficient muscle degeneration and possibly identify pathways that could serve as targets for therapeutic intervention in the treatment of human MCMD.
|Jeudy, Sheila; Wardrop, Katherine E; Alessi, Amy et al. (2011) Bcl-2 inhibits the innate immune response during early pathogenesis of murine congenital muscular dystrophy. PLoS One 6:e22369|
|Wardrop, Katherine E; Dominov, Janice A (2011) Proinflammatory signals and the loss of lymphatic vessel hyaluronan receptor-1 (LYVE-1) in the early pathogenesis of laminin alpha2-deficient skeletal muscle. J Histochem Cytochem 59:167-79|