Molecular remodelling of endothelial cells in response to specific lymphocytes and other signals

Summary This project will reveal novel insights into the role of circulating lymphocytes and other factors in modulating endothelial molecular function, a key determinant in a range of adverse health outcomes, including atherosclerosis and cardiovascular disease.

Project Details

The vascular endothelium is a highly specialized barrier that plays a key role in the regulated migration of leukocyte cells out of the circulation and into peripheral tissues as part of the systemic immune response. In atherosclerosis, this barrier function is impaired leading to uncontrolled leukocyte accumulation and systemic inflammation.

Recent data have shown that cells of the innate immune system, such as monocytes and macrophages, have capacity to develop a non-specific memory in response to inflammatory signals. Termed 'innate immune memory', it is increasingly clear that this is not restricted to cells of the hematopoietic lineage. We have recently demonstrated that endothelial cells of different origins have the capacity to establish innate immune memory following an initial stimulus (viral or bacterial). Further, we have mapped the molecular 'reprogramming' involved in this process, that enables an enhanced response to an unrelated second stimulus.

It is important to note that cells do not act in isolation, and we now aim to explore the impact of a range of human plasma and lymphocyte (white blood cells) protein stimuli on endothelial memory.

This project will involve culturing vascular endothelial cells with plasma from individuals of variable health outcomes (diabetes, obesity, allergic and autoimmune conditions) and endothelial-lymphocyte co-culture experiments. We couple these with state-of-the-art transcriptome and epigenetic profiling. Techniques include cell culture, DNA/RNA extraction, a range of epigenetic approaches, RNA sequencing (RNA-seq) and bioinformatic analysis.

This project will reveal novel insights into the role of circulating lymphocytes and other factors in modulating endothelial molecular function, a key determinant in a range of adverse health outcomes, including atherosclerosis and cardiovascular disease.