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Title: Molecular pathology of glycated extracellular matrix in disease
Author: Dobler, Darin Paul
ISNI:       0000 0001 3426 5793
Awarding Body: University of Essex
Current Institution: The University of Essex pre-October 2008
Date of Award: 2008
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Glycation of the extracellular matrix has been linked to chronic vascular disease and endothelial cell dysfunction. Proper functioning of the ECM requircs both chemical and structural integrity, both of which arc compromised by glycation. The mechanism, extent and functional consequenc·cs of ECM glycation have not yet been clearly defined. The metabolic dysfunction underlying this vascular damage and disruption is unclear. Methylglyoxal, a dicarbonyl glycating agent increased in hyperglycaemia, is known to modify arginine residues in proteins. Increased modification of the vascular basement membrane type IV collagen by methylglyoxal formed arginine-derived hydroimidazolone residues at hotspot sites in RGD and GFOGER integrin-binding sites. Loss of functional contact between integrins and the cxtraccllular matrix activates anoikis and impairs angiogcnesis. Inc~bation of endothelial cclls in hyperglycacmia and cxperimental diabetes in vivo produced the same modifications in vascular collagcn and induced similar responses. Pharmacological scavenging ofmcthylglyoxal prevented anoikis and maintained angiogenesis. In normoglycaemia, thcse responses werc provoked by a cell permeable glyoxalase I inhibitor.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available