Integrins in muscle disease and repair

Divekar, Devina (2014) Integrins in muscle disease and repair. Doctoral thesis, University of East Anglia.

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Abstract

Integrin α7β1 plays an important role in maintaining adult skeletal muscle integrity and like dystrophin, provides anchorage and bidirectional signaling as a laminin receptor. The expression of α7β1 integrin was upregulated upon dystrophin deficiency arguing for the molecular compensation and thus considered as potential
candidate for treatment of Duchenne Muscular Dystrophy (DMD).
The existence of developmentally regulated alternative splice variants makes the α7β1 integrin a complex integrin to study its function in skeletal muscle. In this study we show that increased levels of the adult extracellular variant X2 interfere with muscle integrity, while the presence of embryonic integrin α7 extracellular variant X1 results in
normal skeletal muscle architecture. Furthermore, detailed analysis of mdxα7tg mice suggests that overexpression of integrin α7 made no difference on the dystrophic
phenotype, in fact mdx α7X2 mice show a more severe phenotype compared to mdx mice.
Our study also shed light on the importance of integrin α5 during the development of the skeletal muscle by means of generating conditional knockout (cKO) mice using HSA-Cre and Pax3-Cre promoter systems. Our findings show no obvious difference in the Itga5 cKO when the HSA promoter drives Cre recombinase, however conditional loss under the control of the Pax3 promoter leads perinatal lethality.
In addition we investigate the dosage effect of integrin α5 in integrin α7 knockout (KO) mice to understand the cross talk between these two integrins and to correlate with previous data suggesting a gain of function phenotype by that existence of integrin α5 at the myotendinious junction (MTJ) in α7KO muscle (Nawrotzki et al.,2003)
From our data we know that gene therapy with integrin α7 is a challenge and is not a suitable alternative to cure dystrophy, at least not in mdx mice, we therefore switch
our focus on looking into cell based therapies for DMD by investigating the potential role of perivascular cells (PVCs) using transplantation experiments in mice by artificially inducing muscle damage.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Brian Watkins
Date Deposited: 07 Sep 2015 15:45
Last Modified: 07 Sep 2015 15:45
URI: https://ueaeprints.uea.ac.uk/id/eprint/54271
DOI:

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