Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.695796
Title: Molecular and functional characterisation of KV7 channels in mammalian myometrium during pregnancy and parturition
Author: Mansour, Yosef Tariq
ISNI:       0000 0004 5991 1677
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2016
Availability of Full Text:
Access through EThOS:
Full text unavailable from EThOS. Restricted access.
Access through Institution:
Abstract:
Human parturition is a tightly controlled process, but for some women, aberrations in this timing give rise to dysfunctional labour, including preterm birth and dystocia; such complications are associated with increased risk of neonatal mortality and morbidity. Current management strategies are limited in their effectiveness, requiring further understanding of the pathways governing uterine activity. The KV7 subfamily of voltage-gated potassium channels, composed of KCNQ- and KCNE-encoded subunits, are key regulators of smooth muscle cell membrane excitability in a range of tissues, but their role in uterine contractions has yet to be fully explored. The working hypothesis was that KV7 channels are expressed and functionally active in myometrial tissue at the end of gestation and during labour (term and preterm), and that KV7 channel activators can inhibit myometrial contractility in vivo sufficiently to delay preterm labour. Expression of KCNQ1-5 and KCNE1-5 mRNA and protein was analysed in myometrium from pregnant women before and after the onset of labour. The functional contribution of KV7 channels at term was also investigated. A murine model of RU486-induced preterm labour was used to characterise KV7 subunit expression and investigate the in vivo effectiveness of KV7 activators as tocolytics for the treatment of preterm labour. Protein and mRNA for KCNQ4, KCNE3 were downregulated, while KCNQ3 was increased, after the onset of labour (p<0.05 for all). Application of Kv7 activator and blockers decreased and increased ex vivo myometrial contractility respectively (p<0.05 for all). In preterm murine myometrium, KCNQ4, KCNQ5, KCNE1 and KCNE2 were downregulated during preterm labour (p<0.05 for all). KV7 activators, retigabine and ML213, decreased myometrial activity in vitro and significantly delayed the onset of preterm labour in vivo (p<0.05 for both). These novel data provide proof of concept that KV7 channels can be targeted for tocolysis. Together with a better understanding of the KV7 channel composition in human myometrium, this study is the first step in translation to the human condition of preterm labour.
Supervisor: Taylor, Paul David ; Tribe, Rachel Marie Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.695796  DOI: Not available
Share: