Development of novel macrophage high-throughput cell-based phenotypic assay for drug screening

Research Group

Biomedical Research Group

Proposed supervisory team

Dr Grisha Pirianov

Prof David Leake (University of Reading)

Theme

Translational Biomedicine

Summary of the research project

Background: Macrophages play a critical role in homeostasis and diseases. They can change their phenotype to perform differential activities in different phases of inflammatory response.

Polarized macrophages are broadly classified into two groups:

• classical activated M1 (pro-inflammatory)
• alternative activated M2 (anti-inflammatory).

It has been demonstrated that M1/M2 switch plays critical role in inflammation which is dependent on various factors such as bioavailability of different subsets of monocytes and macrophages, sequential monocytes recruitment into the tissue in the process of inflammation or response to different conditions. Furthermore, the misbalance of M1/M2 switch can lead to chronic inflammatory diseases. Undoubtedly the generation of novel anti-inflammatory drugs regulating M1/M2 switch is an important step for pharmacological intervention of chronic inflammatory-based diseases. Unfortunately, the current drug screening strategies are not based on macrophage polarization. The development of a phenotypic macrophage high-throughput assay will provide a platform for screening of pro or anti-inflammatory properties of the candidate molecule (preclinical drug validation) or FDA approved drugs library and selected compound libraries with known anti-inflammatory activity (clinical drug validation).

Main goal and objectives: The main goal of the study is to develop and validate a novel phenotypic macrophage high-throughput cell-based assay for anti-inflammatory drug screening activity. The two main objectives are:

• to develop a cell-based M0/M1/M2 phenotypic screen
• to investigate the effect of novel small molecules (TLR4 antagonists) and selected compound libraries with known anti-inflammatory activity on M0/M1/M2 screen.

Methodology: Cell culture and cell-based essays, western blotting, ELISA approaches.

Collaborations: This project is based on academic and industrial collaborations with Reading University and Innaxon, UK respectively.

Outcomes: Results from this project will evaluate the potential of the phenotypic macrophage high-throughput assay for drug screening as well as provide important information about the effect of the candidate molecules on macrophage polarisation and will contribute to their preclinical/clinical validation. This will represent a finding of great public and commercial impact as currently there are no macrophage cell-based phenotypic assays for drug screening. The proposed project will have a commercial value and we plan to secure protection of the arising intellectual property.

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.