Characterizing and targeting fibrosis in a model of Lama2-related muscular dystrophy
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Abstract
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.