About the Project
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.
Entry Requirements
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 previous laboratory experience, particularly in cell culture and molecular biology, are particularly encouraged to apply.
How 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 Genetics
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.
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/”
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 www.internationalphd.manchester.ac.uk
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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