Project Abstract

Yvonne Kobayashi is an Associate working in the laboratory of Kevin Campbell at the Wellstone Muscular Dystrophy Cooperative Research Center at the University of Iowa Carver College of Medicine. The longterm goal of this project is to design a therapy for autosomal recessive limb-girdle muscular dystrophy type 2D (LGMD-2D), which is caused by mutations in the α-sarcoglycan gene (SGCA) that lead to progressive muscle fiber necrosis and weakness. α-Sarcoglycan interacts with β-, γ-, and δ-sarcoglycan to form a subcomplex that increases the overall stability of the dystrophin-glycoprotein complex (DGC). ε-Sarcoglycan is a ubiquitously expressed homologue of the muscle-specific α-sarcoglycan, sharing 43% identity and a similar protein structure. Using Sgca-null mice, a mouse model of LGMD-2D, that concomitantly have enhanced muscle expression of a human ε-sarcoglycan transgene, Dr. Kobayashi showed that increased muscle ε-sarcoglycan expression is able to structurally and functionally replace α-sarcoglycan without creating its own pathology. This work suggested a novel therapeutic strategy for LGMD-2D. The goal of this proposal is to examine how ε-sarcoglycan expression levels affect muscle pathology in LGMD-2D, and to pharmacologically up-regulate the expression of ε-sarcoglycan to prevent muscle pathology in α-sarcoglycan deficiency. Dr. Kobayashi will collaborate with and receive training from Steve Moore, MDCRC Co-Director at the University of Iowa, who will contribute his experience in basic, translational, and clinical research on muscular dystrophy, and John Faulkner from the University of Michigan, who will contribute his expertise in physiological analysis of muscle function. Dr. Kobayashi will receive training from Dr. Moore in handling, sectioning, and immunohistochemical analysis of patient biopsies, and from Dr. Faulkner's laboratory for hands-on training in muscle fiber functional analysis. This proposal ties into the overall goal of the parent MDCRC to explore therapeutic strategies for the treatment of various muscular dystrophies, in this case LGMD-2D. Aim 1 will focus on identifying differences in ε-sarcoglycan expression in different skeletal muscles and fiber types, and in muscles subjected to different activity levels in both wild type and Sgca-null mice. This Aim will determine how ε-sarcoglycan levels affect muscle pathology. Some of these same parameters will be further examined in normal human tissue by generating new antibodies specific for human ε-sarcoglycan. Aim 2 will test the ability of various classes of pharmacological agents in Sgca-null mice to up-regulate ε-sarcoglycan expression levels, decrease muscle pathology, and improve muscle function. In summary, these experiments will identify physiological conditions and test pharmacological agents that will upregulate ε-sarcoglycan to prevent muscle pathology in α-sarcoglycan deficiency.