Dissertation/Thesis Abstract

New Congenital Mouse Model to Study Laminin Protein Therapy for Muscular Dystrophy
by Coffey, Caroline B. M., Ph.D., University of Nevada, Reno, 2015, 350; 10001052
Abstract (Summary)

Merosin deficient congenital muscular dystrophy type 1A (MDC1A) is caused by the loss of laminin-211 and laminin-221 heterotrimers which are most abundant in skeletal and cardiac muscle basal lamina; mutations in the LAMA2 gene cause the loss of these laminin isoforms. This absence of laminin-211/221 in MDC1A reduces the capacity for myofiber adhesion, loss of sarcolemmal integrity and subsequently the ability of the skeletal muscle syncytium to generate force in a coordinated and efficient manner. Patients experience progressive muscle wasting which confines them to a wheelchair at an early age and respiratory failure that leads to their untimely death. Currently, there is no effective treatment or cure for this devastating disease. Previous studies have shown that laminin-111, an embryonic form of laminin, delivered before disease onset can reduce muscle pathology and improve viability in the dyW-/- mouse model of MDC1A. These studies suggested that laminin-111 may act to strengthen and reinforce the sarcolemma and provide a protective niche for muscle repair. Since most patients are diagnosed with MDC1A after disease onset, we determined if laminin-111 could be beneficial after disease onset. Our studies suggest dyW-/- mice treated with laminin-111 after disease onset show improvement in muscle function and histology. Results from this study along with an understanding of laminin-111 pharmacokinetics will help pave the way in developing this protein as an exciting potential therapeutic for MDC1A patients. Duchenne Muscular Dystrophy (DMD) is the most common X-linked disease affecting 1 in 3,300 live male births. Patients with DMD suffer from severe, progressive muscle wasting and weakness with clinical symptoms first detected between 2 to 5 years of age; as the disease progresses patients are confined to a wheelchair in their teens and die in their early 20s mainly due to cardiopulmonary complications. DMD is caused by the loss of the sarcolemmal protein dystrophin (427kDa) due to mutations in the dystophin gene. When present, dystrophin acts as a scaffold linking the cell cytoskeleton to the extracellular matrix. This loss of dystrophin in DMD results in patients experiencing greater susceptibility to muscle damage via reduced structural and functional integrity of their muscle. One potential therapeutic avenue that needs to be explored involves increasing the levels of the ?7?1 integrin in order to compensate for the loss of dystrophin. To test this hypothesis, a muscle cell-based assay was developed in order to report ?7 integrin promoter activity with the intent of identifying molecules that promote ?7 integrin expression. Laminin-111 was identified as an enhancer of ?7 integrin expression. Theoretically, the identification of ?7 integrin enhancing compounds that help boost ?7?1 integrin expression as part of drug-based therapies may lead to a novel therapeutic approach for the treatment of this disease. Systemic laminin-111 treatment significantly reduces myofiber degeneration in both forms of MDC1A and DMD muscular dystrophy. This dissertation reinforces the potential of laminin-111 as a systemic protein therapy, capable of restoring sarcolemmal integrity thus reducing muscle disease progression. The importance of ?7 integrin in skeletal and cardiac muscle was highlighted here through the generation of the ?7-/-:: laminin-?2-/- double knockout mouse model. This mouse has never been studied before and could prove to be another important mouse model needed to explore therapeutic avenues for muscular dystrophy.

Indexing (document details)
Advisor: Burkin, Dean J.
Commitee: Baker, Josh E., Burkin, Dean J., LeBlanc, Normand, Verma, Subhash C., Ward, Sean M.
School: University of Nevada, Reno
Department: Cell and Molecular Pharmacology and Physiology
School Location: United States -- Nevada
Source: DAI-B 77/06(E), Dissertation Abstracts International
Subjects: Biology, Molecular biology, Pharmacology
Keywords: Dyw, Laminin-111, Mdc1a, Mdx, Muscular dystrophy, Skeletal muscle
Publication Number: 10001052
ISBN: 9781339413112
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