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Title: Application of proteomics to human hypertrophic cardiomyopathy
Author: Coats, C. J.
ISNI:       0000 0004 7231 2847
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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This work describes a preliminary study to evaluate the use of proteomics in the study of human hypertrophic cardiomyopathy. Both gel and mass spectrometry techniques were used for the identification and analysis of myocardial proteins in whole tissue lysate. Qualitative and quantitative proteomic methods were used to understand disease mechanisms and identify and validate novel biomarkers. Disease caused by mutations in beta myosin heavy chain, MYH7 and myosin binding protein-C, MYBPC3 were studied alongside patients where no genetic variant could be identified. Left ventricular septal myectomy samples showed changes in protein expression compared with control tissue. Novel mutations in MYH7 were confirmed by identification of mutant peptide sequences. Disease mechanisms were investigated by studying interactions between up- and down-regulated proteins involved in various pathways. Enriched protein groups included those involved in cytoskeletal protein binding and energy production. Novel findings included the identification of carbonic anhydrase III in cardiomyocytes. A targeted and multiplexed MRM-MS assay was developed to validate potential biomarkers in tissue and correlated with clinical phenotype. The assay was further applied to screen these biomarkers in urine. Novel findings included increased expression of lumican, a small leucine-rich proteoglycan that controls the assembly of collagen fibres in the extracellular matrix. Lumican concentration was highest in a sub-group of patients with evidence of scarring on cardiac magnetic resonance imaging, making it a potential marker of progressive disease. This is the first comprehensive global proteomic study of human hypertrophic cardiomyopathy. It has identified differences in the expression of several proteins in the myocardium not described previously, but highly relevant to pathophysiology of this disease. A targeted proteomic translational assay, capable of quantitating 35 peptides in less than 10 minutes has been developed.
Supervisor: Elliott, P. ; Mckenna, W. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available