About the Project
Cardiovascular disease (CVD) is the world’s single biggest killer causing 1 in 3 deaths. Drug-induced cardiac damage (e.g. arrhythmias, cardiac hypertrophy, and heart failure) is also a major global issue in drug treatment of chronic disorders (e.g. cancer, CVD, diabetes, depression) and limits drug efficacy and development. We have identified a cardiac-enriched gene named STARS that plays a pivotal role in heart function. STARS knockdown (KD) in zebrafish resulted in dilated cardiomyopathy, decreased ventricular function and arrhythmia, which was reversed by co-injection of SRF mRNA [1]. Cardiac-specific STARS KD in Drosophila rendered the heart arrhythmic [2]. STARS KD in cardiomyocytes renders cells susceptible to oxidative stress-induced cell death [3]. Over-expression of STARS in cardiomyocytes led to hypertrophy [4]. STARS is epigenetically regulated and controlled by the pivotal cardiac factor GATA4 [5]. Therefore STARS is a novel and essential nodal point in cardiac cell survival and remodelling and an attractive therapeutic target. However the mechanism of STARS action and how it is precisely regulated is still unclear.
Our group have recently identified a novel cardioprotective signalling pathway that impinges on diverse disease-related gene networks involving STARS. We have identified an endogenous mediator that modulates several key cardioprotective genes during stress including STARS. In this project, the scholar will use established state-of-the-art in vitro and in vivo approaches (e.g. human iPSC-CM, SiRNA/CRISPR, Seahorse Analyzer), coupled with cardiac disease model systems (cellular hypertrophy, apoptosis, mitochondrial dysfunction, intact Drosophila heart prep, ex-vivo heart prep), to elucidate the mechanisms of STARS in cardioprotection. This is a multi-disciplinary project utilising the strengths at the University of Westminster and two other renowned UK Institutions. They will acquire knowledge in high-profile areas of research (heart disease, cardiotoxicity, metabolism, gen regulation) and cutting-edge techniques. The scholar will be encouraged to present their findings in renowned international conferences (AHA, ESC).
Informal enquiries: Dr Nelson Chong : [Email Address Removed]
References
] Chong, N.W. Kokemoer, AL., Samani, N.J., Shin JT., Shaw, S. (2012) STARS (Striated muscle Activator of Rho Signalling) is essential to maintain cardiac development and function in vivo via a SRF pathway. PLoS One 7, e40966.
[2] Beaumont, K.L., Rosato, E. and Chong, N.W. (2011). Cardiac-specific RNAi knockdown of Abra disrupts heart function and alters lifespan in Drosophila melanogaster. European Heart Journal, 32 (sup. 1), 812.
[3] Fothergill D and Chong NW (2014) STARS SiRNA knockdown altered cardiac hypertrophy associated gene expression in cardiac myoblasts and rendered cells susceptible to hydrogen peroxide induced cell death. Global Heart 9(1S): O067.
[4] Koekemoer AL, Chong NW et al (2009) Myocyte stress 1 plays an important role in cellular hypertrophy. FEBS Lett 583, 2964-2967
[5] Ounzain, S., Kobayashi, S., Peterson, R., He, A., Samani, N.J., Menick, D.R., Pu, W.T., Liang, Q. and Chong, NW. (2012). Cardiac expression of STARS, a novel gene involved in cardiac development and disease, is regulated by GATA4. Molecular and Cellular Biology. 32, 1830-1843.