Characterisation of microRNAs regulated by dihomo-gamma-linolenic acid in macrophages in relation to atherosclerosis
Atherosclerosis, the underlying cause of myocardial infarction, stroke and peripheral vascular disease, is responsible for more deaths in the western world than any other disease with mortality increasing at a marked rate in developing countries.
The economic burden from atherosclerosis and its complications is expected to worsen due to global increase in risk factors such as diabetes and obesity. Atherosclerosis is an inflammatory disorder of large and medium arteries regulated by several cytokines. Manipulating such inflammatory response represents a promising avenue for the prevention and treatment of this disease.
Many important fatty acids, such as dihomo-gamma-linolenic acid (DGLA), act in an anti-inflammatory manner. Unfortunately, the anti-inflammatory effects of DGLA in atherosclerosis along with the underlying mechanisms are poorly understood and further studies are required given their potential for preventing/limiting this disease. Previous studies in the our laboratory using a microRNA (miRNA) array have identified DGLA regulated miRNA in macrophages, a cell type that has been implicated in all stages of atherosclerosis. This PhD project will characterise selected DGLA-regulated miRNAs with focus on validating the action of the fatty acid on their expression by real-time quantitative PCR and extending the studies on the regulation of their expression to other pro-atherogenic and anti-atherogenic factors (e.g. cytokines) together with macrophages from various mouse models of atherosclerosis. In addition, the effect of overexpression and repression of these miRNA on key macrophage processes associated with atherosclerosis will be investigated in vitro, including cell migration, pro-inflammatory gene expression, production of reactive oxygen species, production of pro-inflammatory cytokines, activation of inflammasome, phagocytosis and regulation of macrophage cholesterol homeostasis. The findings will be correlated with potential targets of these miRNAs by bioinformatic and functional analysis.