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Understanding the posttranslational control of inflammatory response.


Faculty of Biology, Medicine and Health

About the Project

The incidence of inflammatory disease in the population is rapidly increasing hence the urgent need to validate novel targets and develop efficient anti-inflammatory drugs. Macrophages are key cells regulating the immune response and initiate critical inflammatory processes such as the activation of the inflammasome, a molecular complex responsible for the release of potent proinflammatory mediators and cell death (pyroptosis). Inappropriate activation of the inflammasome contributes to deleterious inflammatory syndromes including, diabetes, atherosclerosis or cancer. However, our understanding of the intrinsic regulatory mechanisms of inflammasome activation is incomplete thus hindering development of effective interventions for these devastating conditions.

This project will explore the molecular mechanisms of inflammasome activation. It will investigate the cellular signalling mechanisms by which the ubiquitin system mediates this activation in macrophages and delineate the mechanisms that dampen the activity of this inflammatory complex during the resolution phase of inflammation.

This project is ideal for a candidate with strong interests in cell biology and the use of molecular approaches to study human disease-relevant questions. This will involve a significant amount of cell culture, both cell lines and primary cells (murine and human), molecular biology, and imaging, using standard immunostaining techniques but also live cell using confocal microscopy. The PhD student will benefit from a stimulating environment and the cutting-edge facilities at the faculty of Biology Medicine and Health and the world-leading Lydia Becker Institute of Immunology and Inflammation. As a PhD student you will be encouraged to present your research at internal meetings as well as attending international conferences. Please email us if you are interested and would like to know more about the project.

Candidates are expected to hold (or be about to obtain) a minimum upper second-class honours degree (or equivalent) in Biology or a related area / subject. Candidates with experience in molecular biology approaches or with an interest in inflammation and cellular signalling are encouraged to apply.

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Inflammation Sciences.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk


Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Gritsenko A, Yu S, Martin-Sanchez F, Diaz del Olmo I, Nichols EM, Davis D, Brough D, Lopez-Castejon G*. Priming is dispensable for NLRP3 inflammasome activation in human monocytes. Under review in PNAS, 2020*

Tapia V, Daniels M, Palazón-Riquelme P, Dewhurst M, Luheshi M, Rivers-Auty J, Green J, Redondo-Castro E, Kaldis P, Lopez-Castejon G*, Brough D*. The related cytokines IL-1β, IL-18, and IL-1α share related but distinct secretory routes. JBC. 2019. PMID: 30940725.

Green JP, Yu S, Martín-Sánchez F, Pelegrin P, López-Castejón G, Lawrence CB, Brough D. Chloride regulates dynamic NLRP3-dependent ASC oligomerization and inflammasome priming. PNAS. 2018. https://doi.org/10.1073/pnas.1812744115.

Palazón-Riquelme P, Worboys JD, Green J, Valera A, Martín-Sánchez F, Pellegrini C, Brough D, López-Castejón G*. USP7 and USP47 deubiquitinases regulate the NLRP3 inflammasome activation. EMBO Rep. 2018. https://doi.org/10.15252/embr.201744766.

Lopez-Castejon G, Control of the inflammasome by the ubiquitin system. FEBS J. Nov 2019. https://doi.org/10.1111/febs.15118.

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