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Title: Regulation of calcium handling proteins by microRNA-1 in heart failure
Author: Mills, Adam
ISNI:       0000 0004 5989 7131
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Heart failure has a complex pathophysiology, a diverse aetiology, an increasing prevalence and only palliative treatment is currently available. The underlying molecular cause of cardiomyocyte malfunction is not fully understood. MicroRNA-1 is a post transcriptional genetic regulator that is highly expression expressed in the myocardium and has been found to influence cardiomyocyte proteins that are key for maintaining calcium homeostasis and contractility; the sarcoplasmic reticulum calcium transport ATPase (SERCA2a) and the sodium calcium exchanger (NCX). MicroRNA-1 expression is disrupted in both in vivo models and heart failure patients; this makes the impact of altered microRNA-1 expression on the development of heart failure pathophysiology an interesting target for investigation. Using in vitro and in vivo models of heart failure, experiments were conducted to increase microRNA-1 expression by viral or non-viral transfection techniques. This produced a number of interesting results relating to cardiomyocyte function; impaired Beta-adrenoceptor mediated contractility, a hallmark of the heart failure phenotype, was reversed and can most likely be attributed to an increase in cyclic adenosine monophosphate (cAMP) production. SERCA2a driven sarcoplasmic reticulum (SR) calcium loading was improved and a greater release of calcium from the SR was recorded. Questions remain around the mechanism connecting microRNA-1 to these targets, particularly as gene expression was unaffected by increased microRNA-1. Future experiments would focus on bridging this understanding to expand upon these results. The prognostic potential of circulating microRNAs in serum samples taken from a well characterised population of heart failure patients was also investigated. Two separate microarray platforms were conducted and the expression of a shortlist of 15 microRNAs validated further. Unfortunately no microRNA could be identified that could consistently distinguish between good and poor prognosis heart failure patients. This does not discount circulating microRNAs as possible prognostic biomarkers of heart failure, but a different approach would be required for future experiments.
Supervisor: Harding, Sian ; Lyon, Alexander ; MacLeod, Ken Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available