Characterizing and targeting fibrosis in a model of Lama2-related muscular dystrophy
Accorsi, Anthony Andrew
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Laminin-deficient congenital muscular dystrophy 1A (MDC1A) is the second most prevalent congenital muscular dystrophy (CMD) and is due to a defect in the alpha chain of the basement membrane protein laminin-211. This protein serves as the vital link between the muscle cell membrane (sarcolemma) and the extracellular matrix (ECM) via interactions with integrins and a-dystroglycan. Loss of laminin results in impaired myofiber anchoring, structural instability, and a multitude of dysregulated signaling pathways leading to many devastating secondary pathologies. Much of the work to date has focused on studying pathology at the end-stages of disease in mouse models. However, because this is a congenital disease that presents at/soon after birth, the most relevant time periods of study are those that most closely reflect human disease, early development. This thesis will characterize dysregulated pathways throughout development and into end-stage pathology as well as elucidate amelioration of these pathways due to intervention and applicable non-invasive biomeasures to track therapeutic progress. Because this work focuses on secondary manifestations of pathology, the work outlined in this thesis has the potential to be applied to an array of neurodegenerative diseases that are currently without any form of treatment.