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Title:An Alpha7beta1 Integrin-Based Treatment of Muscular Dystrophy
Author(s):Wallace, Gregory Q.
Doctoral Committee Chair(s):Kaufman, Stephen J.
Department / Program:Microbiology
Discipline:Microbiology
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Biology, Molecular
Abstract:Efficient muscle function depends on the attachment of myofibers to their surrounding basement membranes. Two complexes that mediate such interactions in adult skeletal muscles are the alpha7beta1 integrin complex and the dystrophin protein complex. Both act as molecular chains that connect the actin cytoskeleton to laminin in the basal lamina. Disruption of either linkage system leads to muscular dystrophy in humans and mice. To determine if the integrin complex can compensate for the lack of the dystrophin protein complex, transgenic mice were made to produce elevated levels of the alpha7 integrin chain. The transgene was introduced into two dystrophic backgrounds: mdx mice lacking dystrophin and mdx/utr -/- mice lacking dystrophin and a related protein, utrophin. In mdx/utr-/- mice, a twofold increase in integrin was sufficient to reduce muscle degeneration, improve mobility, and extend longevity by threefold. The mechanism of rescue in transgenic mdx/utr-/- mice was independent of the dystrophin-associated proteins and involved the formation of alpha7beta1D integrin heterodimers, which support strong interactions with the cytoskeleton. In contrast, neither a twofold nor a fourfold increase in integrin protein could reduce the dystrophic pathology of mdx mice. These results demonstrate that enhanced expression of the alpha7beta1 integrin ameliorates the severe dystrophy that would otherwise develop in mdx/utr-/- mice, but has no effect on the relatively mild dystrophy of mdx mice. Furthermore, wildtype mice with similarly elevated levels of alpha7beta1 integrin show no overt signs of muscle pathology, indicating that increased integrin is not toxic to muscle. Together, these results substantiate the use of increased integrin as a novel treatment for muscular dystrophy.
Issue Date:2005
Type:Text
Language:English
Description:165 p.
Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2005.
URI:http://hdl.handle.net/2142/86680
Other Identifier(s):(MiAaPQ)AAI3182411
Date Available in IDEALS:2015-09-28
Date Deposited:2005


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