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(BHF Acc) Regulation of vascular inflammation by monocytes and the impact on stroke


Project Description

Monocytes are the primary inflammatory cell in the blood and are central to vascular inflammatory responses and to the progression of vascular disease. A central inflammatory mechanism in monocytes is activation of the NLRP3 inflammasome. The NLRP3 inflammasome is a multi-molecular protein complex that regulates the production of the pro-inflammatory cytokine IL-1β. Preclinical and clinical data support a role for the NLRP3 inflammasome and IL-1β in vascular disease. How the NLRP3 inflammasome is regulated in monocytes is poorly understood. The aim of this project is to elucidate the mechanisms of NLRP3 activation and IL-1β production in monocytes and how this contributes to vascular inflammation during acute cerebrovascular disease.

Here the student will study the regulation of NLRP3 in primary human monocytes and the human monocytic cell line THP1. The student will characterise NLRP3 activation in response to vascular inflammatory stimuli and dissect the mechanisms of activation using cutting edge genome editing technologies and unique pharmacological tools. We have novel unpublished data suggesting the V-ATPase regulates NLRP3 via mTOR. Through understanding this regulatory network the student will deliver new insights into mechanisms of importance for vascular disease and potentially identify molecular targets of therapeutic importance. The student will learn advanced immunological and imaging methods and use these to understand the effects of monocyte NLRP3 activation on vascular inflammatory responses and use preclinical models of stroke to understand how vascular inflammation contributes to acute cerebrovascular disease.

Entry Requirements:
Applications are invited from UK/EU nationals only. Candidates must hold, or be about to obtain, a minimum upper second class (or equivalent) undergraduate degree in a relevant subject (biological sciences). A related master’s degree would be an advantage. Experience working on mechanisms of inflammation is important, as is experience using immunological techniques. Prospective student should have an interest in cardiovascular research.

Applications are welcome for entry points in April 2020 or September 2020. Please select the appropriate entry point when applying.

Funding Notes

This project is to be funded under the BHF Accelerator Award. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BHF Accelerator Award 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

Green JP, Yu S, Martín-Sánchez F, Pelegrin P, Lopez-Castejon G, Lawrence CB, Brough D.
Chloride regulates dynamic NLRP3-dependent ASC oligomerisation and inflammasome priming
Proceedings of the National Academy of Sciences of the USA, 2018, 115:E9371-E9380

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.
EMBO Reports, 2018, 19: e44766.

Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ; CANTOS Trial Group.
Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med, 2017, 377:1119-1131.

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