Investigating the potential of novel mimetic molecules (Toll-like receptor 4 antagonists) to modulate the microphage polarisation

Research Group

Biomedical Research Group

Proposed supervisory team

Dr Grisha Pirianov

Dr Nicholas Pugh

Theme

Cardiovascular, Translational Biomedicine

Summary of the research project

Background: 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.

Where you'll study

Cambridge

Funding

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 as they become available.

Next steps

If you wish to be considered for this project, you will need to apply for our Biomedical Science PhD. In the section of the application form entitled 'Outline research proposal', please quote the above title and include a research proposal.