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Understanding how inflammation affects brain disease


Project Description

We know that both peripheral and central inflammation influence neurological disease. This influence progresses and worsens diverse brain diseases, but the mechanisms involved are poorly understood. Inflammasomes have become recognised as important regulators of inflammation and contributors to disease and are emerging as new therapeutic targets. Here, using unique models and tools developed by our laboratories we aim to elucidate mechanisms of activation for the NLRP3 inflammasome, which is strongly implicated in non-communicable disease. We will determine consequences of NLRP3 inflammasome activation in the brain and establish how systemic illness primes inflammasome-dependent inflammation in microglia leading to greater disease severity and poorer outcome.

Funding Notes

This project has a Band 2 fee. Details of different fee bands can be found on our website (View Website). To apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website). Please select PhD Neuroscience on the application form.

Applicants are encouraged to contact the Principal Supervisor directly to discuss the project. Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with experience in neuroscience or with an interest in immunology are encouraged to apply.

References

Baldwin AG, Rivers-Auty J, Daniels MJD, White CS, Schwalbe CH, Schilling T, Hammadi H, Jaiyong P, Spencer NG, England H, Luheshi NM, Kadirvel M, Lawrence CB, Rothwell NJ, Harte MK, Bryce RA, Allan SM, Eder C, Freeman S, Brough D.
New boron based inhibitors of the NLRP3 inflammasome
Cell Chemical Biology, 2017, in press

Daniels MJD, Rivers-Auty J, Schilling T, Spencer NG, Watremez W, Fasolino V, Booth S, White CS, Baldwin AG, Freeman S, Wong R, Latta C, Yu S, Jackson J, Fischer N, Koziel V, Pillot T, Bagnall J, Allan SM, Paszek P, Galea J, Harte MK, Eder C, Lawrence CB, Brough D. Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models. Nature Communications, 2016, 7:12504

Martín-Sánchez F, Diamond C, Zeitler M, Gomez-Sanchez A, Baroja-Mazo A, Bagnall J, Spiller D, White M, Mortellaro A, Peñalver M, Daniels MD, Paszek P, Steringer JP, Nickel W, Brough D*, Pelegrín P*. Inflammasome-dependent IL-1β release depends upon membrane permeabilisation. Cell Death and Differentiation, 2016, 23:1219-31
(*Joint senior and corresponding author)

Denes A, Coutts C, Lénárt N, Cruickshank SM, Pelegrin P, Skinner J, Rothwell N, Allan SM, Brough D. AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3. Proc Natl Acad Sci, 2015, 112: 4050-4055

Baroja-Mazo A, Martín-Sánchez F, Compan V, Gomez AI, Barberà-Cremades M, Yagüe J, Ruiz-Ortiz E, Antón J, Buján S, Peñalver-Mellado M, Brough D, Aróstegui JI, Pelegrín P. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nature Immunology, 2014, 15:738-748

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