INTEGRIN A7 CRISPR MUTATION IN A ZEBRAFISH MODEL OF CONGENITAL MUSCULAR DYSTROPHY

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Congenital muscular dystrophies (CMDs) belong to an incurable group of muscular disorders called muscular dystrophy. CMD is characterized by muscle weakness, degeneration, and sometimes associated with brain involvement that appears at birth or during early infancy. There are different forms of CMDs based upon the primary genetic defect; one of them is linked to the disruption of muscle cell adhesion receptor, integrin a7 (Itga7). Itga7 is one of the primary transmembrane “canonical” receptors of Laminin-211 and localized to the sarcolemma in skeletal and cardiac muscle cells. It plays a major role in anchoring the sarcolemma to the basement membranes (BMs) in the extracellular matrix (ECM). This anchoring allows the muscle to function properly and allows “inside-out” and “outside-in” signaling through Itga7. Generally, the integrin family has long been known to be involved in various diseases. Unfortunately, due to a lack of understanding, such rare diseases remain very difficult to diagnose and treat. We are interested in understanding this form of muscular dystrophy, how muscle detaches and adapts to pathological conditions. Recently, reverse genetic approaches in zebrafish research have become more popular and valuable with new technologies such as CRISPR-Cas9 technology. Here, we utilized a CRISPR/Cas9 system to generate a targeted itga7 mutation in the zebrafish model. We did this to enhance our understanding of congenital muscular dystrophy with Itga7 deficiency, and attempt to provide a valuable outcome that improves the quality of life for the individual with such disorder as well as toward finding a potential therapy. Using this approach, we showed that itga7 mutant loss muscle-ECM adhesion and loss muscle membrane integrity in the detached fibers only. We showed a vital role of NAD+ in ameliorating muscle degeneration. We also found that targeting the activity of Lysyl-oxidases (LOX) significantly reduces dystrophy in our mutant. The results presented in this dissertation reflect the important role of Itga7 in muscle health and the importance of maintaining muscle homeostasis in an in vivo model of congenital muscular dystrophy with Itga7 deficiency.

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