Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.666657
Title: The regulation and role of MS1 in the cardiac stress response
Author: Fothergill, Daniel Philip
ISNI:       0000 0004 5356 0909
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2015
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Abstract:
Ischaemia reperfusion injury results in metabolic disruption in cardiac cells, potentially leading to cell death and ultimately heart failure. The regulation of the cellular response to ischaemia reperfusion is not fully understood. Previously, the muscle-enriched protein MS1 was shown to be upregulated immediately after physiological and pathological muscle stimulation, possibly acting in the early phase of the stress response. The aims of this work were two-fold. Firstly, to identify transcription factors binding the UP2 site, an evolutionarily conserved putative regulatory region upstream of the MS1 transcriptional start site. In silico analyses were conducted to identify candidate transcription factors, before in vitro assays using H9c2 cardiomyoblasts were used to confirm binding of the identified factors. It was demonstrated that the Ets transcription factors Elf1 and Fli1 can bind the site in vitro, and that Fli1, in concert with GATA2, can modulate MS1 and UP2 expression. Secondly, it was shown that MS1 mRNA and protein are upregulated in response to simulated ischaemia reperfusion in vitro in a similar time-course to its upregulation in pathologically stressed rodent hearts and physiologically stressed human skeletal muscle. In addition, Elf1 knockdown ameliorated this response. It was also demonstrated that MS1 knockdown sensitised cells to oxidative stress. Overall, the findings suggest that MS1 is up-regulated in response to a simulated ischaemia reperfusion protocol in H9c2 cells, and this contributes to the protection of cells against oxidative stress. This response may be facilitated in part by the action of Ets proteins acting at the UP2 site. This thesis provides novel evidence for the involvement of MS1 in cardiomyocyte responses to reperfusion injury, possibly via UP2, and in the cellular protection against oxidant-induced cell death.
Supervisor: Herbert, Karl; Codd, Veryan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.666657  DOI: Not available
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