Novel anti-inflammatory agents targeting atherosclerosis development in diabetes

Inflammatory pathways are a key contributor to diabetic vascular disease, including atherosclerosis. Underlying the development of vascular disease are pathological processes including low-grade inflammation, vascular smooth muscle cell proliferation and endothelial cell dysfunction. These processes are largely driven by hyperglycemia in diabetes, which modulates key growth factors and cytokines, including TNFα and PDGF. Specific targeting of these factors however is problematic because of the important function that both of these molecules play in normal physiology. Previous work in the laboratory has identified a family of small endogenous molecules called Lipoxins that are effective in attenuating pathological growth factor and cytokine signalling in vascular cells. Recent work from our group also demonstrated Lipoxins reduce the recruitment of macrophages to the vessel wall. This project will investigate the molecular mechanisms by which Lipoxins protect against atherosclerosis through the use of more stable mimetics of Lipoxins and various molecular approaches. Project: Pro-resolvins as anti-inflammatory agents: a novel treatment approach to protect against the development of diabetic atherosclerosis. The mechanism of action of Lipoxin A4 against atherosclerosis will be assessed in the ApoE -/- mice that have been made diabetic with streptozotocin (STZ), a model that is prone to the development of atherosclerosis and diabetic kidney disease (see other project). These mice will be crossed with the FPR2 KO mice. FPR2 is the receptor to which Lipoxins bind, and bias the receptor towards anti-inflammatory signalling. In addition, ApoE KO mice in which the receptor has been specifically deleted in myeloid cells will also be used to determine whether the protective effects of Lipoxins are via direct binding to macrophages, or through other cell populations. Aortae will be collected from mice and assessed for atherosclerosis. Lesion size, morphology and phenotype will be examined by histological analysis. Gene expression analysis by RT-qPCR, ELISA for various markers of inflammation, ROS, and cytokine analysis. Depending on progress, there is also the opportunity to perform single-cell RNA-seq analysis on vascular cells of the aorta. For potential PhD students, there is also the potential to study plaque rupture. Methods include animal studies, various in vitro molecular techniques, RT-qPCR, western blots, in-cell westerns, ELISA, immunofluorescence analysis, genetic manipulation (transfection: RNAi, CRISPR) and reporter analysis. The animal studies will also provide opportunities for performing spatial transcriptomics. Top up scholarships may be available on selected projects.