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Title: Investigating telomere length dynamics in human endothelial cells
Author: Patel, Meeta S.
ISNI:       0000 0004 7964 1010
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2019
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Numerous previous studies have shown an association between shorter TL and CAD. Prospective and family-based studies have suggested that shorter TL precedes disease onset. Recent genetic studies have provided evidence to support causality, however the biological mechanism is not understood. There is evidence that catastrophic telomere loss induces endothelial dysfunction through senescence. Such changes in TL do not reflect the modest changes observed at an inter-individual level. The aim of this study was to develop a model system in which TL could be manipulated to investigate potential mechanisms through which TL modulates disease risk. The model utilised the addition of a removal TERT transgene (encoding the catalytic subunit of telomerase, which is normally repressed in somatic cells) to enable TL lengthening or stabilisation in endothelial cell lines. Removal of TERT, through Cre excision at different time points, would allow the generation of subcultures with short and long TL in the absence of potential confounding factors. In total TERT was transduced into nine HUVEC lines, four successfully immortalised and showed TL stabilisation. Three lines stabilised with relatively long TL. One of these lines was taken forward to generate long and short TL subcultures which were tested with and without the presence of a pro-inflammatory stimulus, for markers of endothelial dysfunction. Cells with shorter TL displayed differences in basal expression of the cellular adhesion molecule ICAM-1 at both an mRNA and protein level. Cells with shorter TL were further shown to recruit higher numbers of monocytes using an in-vitro cellular adhesion assay. It was further shown that these differences are not the result of inducing senescence in these cells. This data provides preliminary evidence that TL may regulate monocyte adhesion to endothelial cells, contributing to the early stages of atherosclerosis and providing a potential mechanism through which TL contributes to disease risk.
Supervisor: Codd, Veryan ; Samani, Nilesh Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available