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Title: Investigating the role of Rho Kinase (ROCK) in the wall of the embryonic and adult heart
Author: Bailey, Kate Elizabeth
ISNI:       0000 0004 7228 0275
Awarding Body: University of Newcastle upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2016
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Congenital heart defects are relatively common, affecting over 1% of live births, while adult heart disease is the main cause of death in the UK. Defects acquired during fetal development can have a lasting detrimental effect on adult heart function. Therefore, understanding the underlying mechanisms involved in cardiac development and disease progression are of particular importance. Rho Kinase (ROCK) is expressed in the heart during development and has many cellular functions including cell polarity, proliferation, apoptosis, migration and cytoskeletal arrangement. ROCK is required for heart development to occur normally, however, the exact function of ROCK within the developing cardiomyocytes remains unknown. Transgenic mouse models using Cre-LoxP technology have been utilised to downregulate ROCK specifically in the ventricle of the heart. Downregulating ROCK specifically in the cardiomyocytes results in the development of a number of heart defects including an abnormally thin myocardium, as well as disruption in the arrangement of the cardiomyocytes. Interestingly, these mice survive into adulthood allowing us to investigate the effect developmental ROCK downregulation has on the adult heart. Histological analysis shows that these hearts develop hypertrophy and fibrosis as well as cardiomyocyte disarray. Immunohistochemistry and TEM analysis showed that adult hearts also had disrupted sarcomeres and an increase in autophagy vesicles. Magnetic resonance imaging studies have shown that the function of these hearts is reduced due to increased thickening and rigidity of the myocardial wall; characteristics associated with the development of hypertrophic cardiomyopathy. This thesis demonstrates that downregulating ROCK specifically in the cardiomyocytes during heart development disrupts early sarcomere formation due to reduced troponin I phosphorylation. The abnormal sarcomere formation is thought to stress the cell and hence affect cell cycle regulation, resulting in an increase in expression of the p53/p21 pathway, which temporarily halts cell cycle progression. Additionally, p53 signalling leads to an increase in autophagy during this same time point. This suggests that the downregulation of ROCK in a cell activates p21 as a cell survival mechanism in which the autophagy pathway is also triggered in an attempt to recycle damaged or disrupted sarcomeric proteins. This is a temporary survival mechanism as p21 expression returns to normal by E17.5. The delayed cell cycle progression hence reduces the overall number of cardiomyocytes in the mutant hearts and this is then overcome through the hypertrophic growth of the cardiomyocytes. This in the long term results in the development of HCM.
Supervisor: Phillips, Helen ; Henderson, Deborah Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available