Our overall objective is to develop a novel therapeutic intervention that increases muscle membrane repair and modulates inflammation away from a chronic response in LGMD2B to improve overall patient outcomes.
The skeletal muscles of patients with LGMD2B have defects in repair leading to heightened chronic immune response. We will define Gal-1 as a favorable suppressor of LGMD2B disease pathogenesis and further define the mechanism through which these changes are accomplished. Since Gal-1 can be found in monomeric or dimeric forms (each known to have unique functions), it is crucial to define the biochemical functions of Gal-1 responsible for varying therapeutic benefits in LGMD2B. Our recently published preliminary data using cell and skeletal muscle fibers of dysferlin-deficient models suggest recombinant histidine-tagged human Gal-1 (rHsGal-1) increases myogenesis and improves membrane repair. Additionally, we show data suggesting that the carbohydrate recognition domain of Gal-1 mechanistically interacts with glycosylated cell membrane proteins to provide membrane stability.
A significant disease characteristic in LGMD2B is chronic muscle inflammation due to either activation of the NF-B pathway and/or through an impaired transition from pro-inflammatory, cyto-destructive (M1) macrophages to macrophages with regenerative anti-inflammatory capacity (M2) is. We will measure the extent of M1 to M2 macrophage polarization with Gal-1 treatment. The objective of this proposal uses models of LGMD2B to test the hypothesis that Gal-1 treatment decreases disease pathology by increasing membrane repair capacity and decreasing chronic inflammatory response. Our ultimate goal is to develop a novel therapeutic intervention that improves overall patient outcomes.