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Using an activator of hERG (RPR-260245) in a model of acquired and inherited Long QT syndrome type 2

Resource type
Thesis type
(Thesis) M.Sc.
Date created
2017-07-17
Authors/Contributors
Abstract
The human ether-a-go-go related gene (hERG) channel is the molecular correlate of the rapid delayed rectifier current (IKr); its dysfunction causes Long QT syndrome type II (LQT II). RPR-260245 (RPR) is an activator of hERG that increases hERG current by slowing deactivation. Thus, it represents a potential treatment strategy for LQT. However, only few studies have addressed its impact on cardiac physiology. We used electrophysiology techniques in Xenopus Laevis oocytes and optical mapping in induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) to test the effects of RPR on hERG and on the cardiac action potential. We show that RPR has little effect on the cardiac AP in WT iPSC-CMs but demonstrate a partial rescue in our model of acquired LQT (aLQT) under dofetilide block and a partial rescue in our model of LQT II. Finally, RPR significantly increases protective hERG current, especially in instances of the R56Q mutation.
Document
Identifier
etd10239
Copyright statement
Copyright is held by the author.
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This thesis may be printed or downloaded for non-commercial research and scholarly purposes.
Scholarly level
Supervisor or Senior Supervisor
Thesis advisor: Tibbits, Glen
Thesis advisor: Claydon, Thomas
Download file Size
etd10239_VSergeev.pdf 3.42 MB

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