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Altering Inhibitory Extracellular Matrix Promotes Remyelination

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ucalgary_2015_keough_michael.pdf (47.16Mb)
Advisor
Yong, V. Wee
Author
Keough, Michael
Accessioned
2015-07-02T18:55:04Z
Embargolift
10000-01-01
Issued
2015-07-02
Submitted
2015
Other
remyelination
oligodendrocyte
multiple sclerosis
chondroitin sulfate proteoglycan
Subject
Neuroscience
Type
Thesis
Metadata
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Abstract
Remyelination is the generation of new myelin sheaths after injury, and is accomplished by oligodendrocyte precursor cells (OPCs) that proliferate, migrate, and differentiate into myelin-forming oligodendrocytes. A number of lesion-associated factors have been identified that interfere with the remyelination response. Chondroitin sulfate proteoglycans (CSPGs) are a family of extracellular matrix molecules that provide structural rigidity to tissues and act as signalling molecules to neurons and glia in the developing nervous system. After injury, CSPGs become highly upregulated by astrocytes as part of the glial scar and restrict axonal regeneration. The role of injury-induced CSPG deposition on OPCs and remyelination is far less understood. In this thesis, I characterized a potent inhibitory phenotype of murine OPC adhesion and process outgrowth cultured on CSPGs in vitro. I explored the various mechanisms underlying this inhibitory response, including candidate receptors, downstream signalling molecules, and structural ligands on CSPGs through selective enzymatic degradation. I screened 245 orally available, Health Canada approved medicines for their ability to overcome OPC process outgrowth in the presence of CSPGs, and found a persistent inhibitory phenotype for all drugs tested. Lastly, I assessed the utility of a novel CSPG synthesis inhibitor, fluorosamine, and found that it reduced CSPG synthesis by astrocytes, resulting in a more permissive environment for OPC growth in vitro. Following experimental demyelination with lysolecithin in vivo, fluorosamine treatment reduced the deposition of CSPGs and enhanced OPC maturation and remyelination. Altering the inhibitory microenvironment after injury may be beneficial for promoting repair in a number of neurological diseases.
Embargoterms
indefinite
Corporate
University of Calgary
Faculty
Graduate Studies
Doi
http://dx.doi.org/10.11575/PRISM/24777
Uri
http://hdl.handle.net/11023/2327
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