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Epigenetic regulation in heart failure and cardiac sudden death


Project Description

A large proportion of heart failure patients die from cardiac sudden death (SCD), a direct result of lethal ventricular arrhythmias, which is the principal cause of mortality from heart disease worldwide and remains a major unresolved public health problem. In addition, the incidence of SDC has become increasingly aware in young people having intense physical exercise, likely due to hypertrophic cardiomyopathy and high sympathetic tone. Despite enormity and severity of this life-threatening condition, our understanding of fundamental mechanisms, particularly those involving transcriptional regulation and epigenetic modification of the related genes underlying the pathology of heart failure and SCD remains limited.

Emerging evidence suggests that epigenetics plays a major role in gene regulation in heart failure. Epigenetics refers to the heritable regulation of gene expression through modification of chromosomal components without an alteration in the nucleotide sequence of the genome. Three different types of epigenetic variations are known to alter gene expression: modification of histone proteins, methylation of genomic DNA and regulatory noncoding RNAs.

In the proposed project, we aim to use systematic approaches to analyse the profiles of DNA/RNA methylation and histone modification between normal and heart failure/arrhythmic hearts. Thereafter, taking observed changes for further investigations to determine whether these changes are causes or consequences of the disease. Further investigations will take place in genetically-modified animal models and various cellular models, including human cardiomyocytes derived from iPSCs (induced pluripotent stem cells) in the condition of heart failure and induced lethal ventricular arrhythmias.

This project will provide a comprehensive training for a PhD student in systematic and translational medicine with a wealth of molecular and cellular approaches, including next generation RNA sequencing, genome-wide methylation screening and Chip-seq etc, in vivo cardiac functional study (echocardiography, electrocardiography and various surgical procedures) and computational simulation methods.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Informal enquiries may be made directly to the primary supervisor.

References

Myerburg, Robert J. "Cardiac Arrest and Sudden Cardiac Death" in Heart Disease: A Textbook of Cardiovascular Medicine, 7th edition. Philadelphia: WB Saunders, 2005.

Movassagh M, Choy MK, Goddard M, Bennett MR, Down TA, Foo RS.

Differential DNA methylation correlates with differential expression of angiogenic factors in human heart failure. PLoS One. 2010;5:e8564.

Tingare A, Thienpont B, Roderick HL. Epigenetics in the heart: the role of histone modifications in cardiac remodelling. Biochem Soc Trans. 2013 Jun;41(3):789-96.

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