Carberry, Steven (2014) Proteomic Profiling of the mdx Animal Model for Duchenne Muscular Dystrophy. PhD thesis, National University of Ireland Maynooth.

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Abstract

Duchenne Muscular Dystrophy is a lethal childhood disorder which results in progressive muscle weakness and wasting due to genetic abnormalities in the dystrophin gene. While the primary abnormality lies with the loss of the crucial membrane cytoskeletal protein dystrophin and the reduction of its associated glycoprotein complex, secondary alterations in cellular signalling, ion homeostasis regulation and metabolic pathways lead to fiber degeneration and subsequent fibrosis. These changes result in loss of ambulation and sufferers being wheelchair bound in early adulthood. Severe diaphragm and cardiac complications in later life tend to be fatal. The aim of this project was to create a detailed proteomic profile of differentially affected dystrophic tissues using the mdx mouse model; from severely dystrophic diaphragm; moderately affected hind limb to naturally protected interosseus muscle were used to investigate the pathogenesis of the disease. Proteomic analysis of the muscle subtypes indicated that skeletal muscles are differentially affected by the absence of dystrophin protein. Naturally protected interosseus exhibited very little histological and proteomic changes. In contrast to the moderately affected mdx hind limb muscles, the dystrophic diaphragm exhibits severe symptoms of skeletal muscle fiber degeneration that more closely resembles that of the neuromuscular pathology exhibited in Duchenne patients than any other muscle. Novel molecular insights into dystrophic changes suggest increased cellular stress, impaired calcium buffering, cytostructural alterations and disturbances of mitochondrial metabolism in dystrophin-deficient muscle tissue. Thus, the absence of the dystrophin isoform Dp427 and resulting reduction in dystrophin-associated glycoproteins in the dystrophic sarcolemma seems to trigger a variety of secondary abnormalities in muscular dystrophy. This work has successfully established a detailed biomarker signature that maybe used to evaluate new treatments, improve understanding of the pathobiochemical process and supports the use of mdx mouse as a suitable model for Duchenne muscular dystrophy.

Item Type:	Thesis (PhD)
Keywords:	Proteomic Profiling; mdx Animal Model; Duchenne Muscular Dystrophy;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	5438
Depositing User:	IR eTheses
Date Deposited:	29 Sep 2014 16:05
URI:
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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