Interaction between innate immune activation and endothelial cells, linked to adverse cardiovascular events

Description

The complement system is a key component of the immune response. Maintaining a balance between activation and inhibition of the complement system is key to preserving tissue homeostasis and enabling immune surveillance. Several elements can disrupt this delicate balance, and these defects are exacerbated with age. Indeed, specific components of the classical and alternative pathways are significantly higher in the plasma of older patients. Equally important are so-called inflammasomes; multi-protein complexes that recognise microbe-associated microbial patterns (MAMPs) and danger-associated molecular patterns (DAMPs) to induce inflammation and activation of necessary immune cells. As with the complement system, inflammasome activity is linked to age-related inflammation (Inflammaging), and contributes to age-related disease development. Further ageing of endothelial cells (ECs), which line blood vessels and control vascular homeostasis via unique characteristics as gatekeepers of vasculature leads to endothelial dysfunction, characterized by reduced vasodilation, a proinflammatory state and prothrombic properties, increasing risk of disease development and progression.

We will identify how ageing impacts on complement activity, inflammasome activation and endothelial cell function and how the complex interplay underpinning these interactions may affect the physiological roles they are responsible for. The primary, aims are as follows:

Link complement activation, with its deposition on ECs, inflammasome activation, EC responses and the induction of pro-inflammatory transcriptional cascades in vitro.

In preclinical models, assess the impact of complement and inflammasome activation on vascular function.

Utilising a combinatory approach to deliver a complete picture of molecular mechanisms involved, this project will identify the interaction between activated complement, endothelial function and inflammasome activation and establish novel host mechanisms associated with age-related illnesses central to disease outcomes. Furthermore, identifying complement/inflammasome-associated risk profiles will allow patient stratification and identify targets for individualised and target-directed therapeutics, already tested in vitro.

The project is suited to a student with at least a good B.Sc. Upper Second in Biological or Life Sciences (particularly Pharmacology).