Coronary artery disease: Novel therapeutic targets (multiple projects)

The underlying cause of coronary artery disease (CAD) is atherosclerosis – a maladaptive inflammatory condition driven primarily by macrophages, ultimately resulting in life-threatening cardiovascular events such as heart attacks and stroke. As the atherosclerotic plaque progresses, inflammatory and macrophage cell death pathways drive the formation of complex, unstable and rupture-prone lesions with large necrotic core(s). The persistent hyperactivation of the innate immune system is termed trained immunity and is thought to contribute to the development of the atherosclerotic plaque. Project 1: Trained Immunity in Atherosclerosis – A role for RIPK1? Receptor-interacting serine/threonine Protein Kinase 1 (RIPK1) is a central regulator of inflammatory cell function that coordinates inflammation, apoptosis and necroptosis in response to inflammatory stimuli. Recently, we found that silencing RIPK1 gene expression (using anti-sense oligonucleotides; ASOs) reduced atherosclerosis in mice (Karunakaran et al, Circulation, 2021). In this project, we will investigate how RIPK1 regulates trained immunity in atherogenic macrophages. Project 2: Macrophage and/or VSMC Necroptosis in Atherosclerotic Plaque Rupture RIPK1, and its downstream targets, RIPK3 and MLKL, orchestrate a pro-inflammatory cell death pathway, called necroptosis. We have previously shown a role for necroptosis in atherosclerosis plaque formation (Karunakaran et al, 2016), however, the cell-specific roles of RIPK1/MLKL or necroptosis in early versus advanced rupture-prone plaques are unknown. Using a suite of cutting-edge mouse models, along with tandem stenosis surgery, we will elucidate the cell-specific roles of RIPK1/MLKL in plaque rupture. Project 3: Macrophage PAR2 Antagonism in Early Atherosclerosis Protease-activated receptor-2 (PAR2) is a membrane-bound transmembrane receptor that has been implicated in multiple inflammatory diseases, including atherosclerosis. Previous reports indicate that deletion of PAR2 and/or bone marrow transplantation of PAR2 KO cells in atherosclerotic mice is protective (Hara et al 2018; Jones et al, 2018). In our atherosclerotic model, we have identified that therapeutic antagonism of PAR2 reduces atherosclerosis. In this project, you will investigate the mechanisms of PAR2 signalling in macrophages that drive atherosclerosis, and whether PAR2 antagonism reduces macrophage inflammation in the context of atherosclerosis. Skills, Techniques & Prerequisites: Histology & tissue staining, Aseptic cell culture, siRNA transfections, western blotting, ELISAs and qPCR. Atherosclerosis mouse models. Individuals who are enthusiastic, with a strong work ethic and willing to work conscientiously to achieve project goals are encouraged to apply.