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Title: A study of telomere and telomerase biology in the dog and cat
Author: McKevitt, Tom Patrick
ISNI:       0000 0001 3625 3016
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2004
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The primary aims of this project were to carry out a comprehensive investigation of telomere and telomerase biology in the dog and cat, and more specifically to investigate the potential of telomeres and telomerase as targets for novel cancer chemotherapeutics. The first experiments carried out were concerned with investigating mean telomere lengths in a wide age and tissue range of both the dog and cat. The protocol used for telomere length assessment was based on a DNA probe, Southern Blot and chemiluminescent technique referred to as Terminal Restriction Fragment analysis. Telomere lengths in peripheral blood samples taken from 112 dogs and 30 cats were found to range from 4.7 to 20.6 kb, and 9.6 to 23.5 kb respectively. These are similar to telomere lengths typically found in human samples (5-15 kb). The telomere lengths in a panel of normal canine and feline organ samples, tumour samples, and primary fibroblast cultures also did not differ significantly from these values. Telomere lengths decreased significantly with increased age in both species, and whilst gender did not have a significant effect in either species, an intriguing finding was that breed of pedigree dog had a significant effect on telomere length. Primary canine and feline fibroblasts were found to cease replicating and assume a senescent phenotype in vitro after an average of 10 and 16 population doublings respectively. Over the course of these population doublings, telomere attrition was shown to occur in both canine and feline cells, and averaged 175 and 130 bp/cell division respectively. In summary, telomeres in the dog and cat are of a similar size to that found in humans, and telomeric attrition has been shown to occur in both species in vivo and in vitro. Furthermore, loss of telomeric sequence is associated with the triggering of a senescent phenotype in both canine and feline fibroblasts in vitro. Telomerase activity studies used a commercially available assay, referred to as the Telomeric Repeat Amplification Protocol (TRAP). Telomerase activity was strongly down regulated in a wide range of somatic tissues of the dog and cat. Conversely, telomerase activity was detected in all canine and feline tumours assayed (19/19), and was also present in a panel of immortalised canine cell lines. These data linked telomerase with immortalisation and malignancy in the dog and cat, and have identified telomerase as a potential target for novel cancer ehemotherapeutics in companion animals. A pilot study to assess the efficacy of a reverse transcriptase inhibitor (azidothymidine triphosphate) as a telomerase inhibitor in two canine telomerase dependant cell lines produced inconsistent inhibition of telomerase and no discernable effect on telomere lengths. However, future use of this drug in combination with agents that utilize different modalities for targeting telomerase may produce more favourable results.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available