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Title: The role of MKK7 in heart disease
Author: Sims, Clive
ISNI:       0000 0004 8504 8790
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2019
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MKK7, part of the MAP kinase pathway of signal transduction, was originally though to promote a heart failure phenotype however subsequently, MKK7 was shown to be cardio-protective. We know that this is through prevention of hypertrophy, fibrosis and arrhythmias however whether MKK7 is involved in responding to oxidative stress is unknown. Previous work has failed to address this in animal models or in a human relevant context. Using a ventricular cardiomyocyte specific MKK7 knockout mouse line (MKK7CKO) and enhanced CRISPR/Cas9 mediated MKK7 knockout human embryonic stem cell derived cardiomyocytes (MKK7 KO hESC-CMs), we aimed to gain further understanding of the mechanism of the cardio-protective functions of MKK7 regarding oxidative stress. We found that MKK7 is not required for maintenance of stem cell pluripotency marker expression nor cardiac differentiation. This was the first, thoroughly efficient use of CRISPR/Cas9 to create a human relevant MKK7 KO cell line. Using a pressure overload model and an ischaemia model on our MKK7CKO mice, we investigated how MKK7 functions against two different heart insults. We also attempted to mimic these conditions in vitro by stressing our MKK7 KO hESC-CMs with hypertrophic and oxidative stress stimuli. We found that MKK7 does indeed provide cardio-protection potentially involving maintenance of anti-oxidant gene expression and prevention of cell death, in addition to the protection against hypertrophy, interstitial fibrosis and arrhythmias as shown in our previous work.
Supervisor: Wang, Xin Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Stem cells ; CRISPR ; MKK7 ; Cardiomyocytes