Toll-like receptors (TLRs) serve as pattern recognition receptors within the immune system. Among these receptors TLR4 is activated in response to bacteria and other non-bacterial ligands such as heat shock proteins, small fragments of hyaluronan, and even oxidised low density lipoproteins (oxLDL) in immunocompetent cells. TLR4 expression has been described in monocytes and microphages. TLR4 and different macrophage subsets have been shown to be implicated in inflammatory related diseases suggesting that understanding mechanisms of modulation of TLR4 signalling may be of great importance for pharmacological treatment of atherosclerosis.
Although existing TLR4 antagonists have been discontinued from clinical trials due to lack of efficacy, recently, a novel compound family designed as small molecule TLR4 antagonists have been developed to specifically modulate TLR4 signalling. We have recently shown that one of these molecules (AXO-102) negatively regulated in vivo and in vitro TLR4 signalling in vasculature and inhibited early rupture and incidence of aneurysms formation.
Main goal: This project will investigate the potential of IAXO-102 and other mimetic molecules to modulate the macrophage polarisation (formation of specific subsets) in response to sterile inflammation.
There are three main objectives:
1. To investigate the effects of TLR4 sterile ligand agonists (small fragments of hyaluronan and oxLDL) on TLR4 expression and activation on the macrophage polarisation. 2. To examine the effects of TLR4 sterile ligand agonists to stimulate production of TLR4-dependent pro-inflammatory proteins on the macrophage polarisation. 3. To investigate the potential of novel molecule TLR4 antagonists to modulate TLR4 signalling in relation to microphage polarisation.
Methodology: Cell culture and cell-based essays, western blotting, ELISA and antibody array approaches.
Collaborations: This project is based on academic and industrial collaborations with Reading University and Innaxon, UK respectively. Outcomes: The results from this study will validate the potential of novel TLR4 antagonists as candidates for pre-clinical studies for pharmacological intervention of atherosclerosis.
This project is self-funded. Details of studentships for which funding is available are selected by a competitive process and are advertised on our jobs website (View Website) as they become available.