Investigating inflammasome regulation in human myeloid cells

two female students in labcoats using a pipette dropper to add a substance to a test tube

CEM Funded Opportunity

Investigating inflammasome regulation in human myeloid cells

Project Description

Inflammasomes are protein complexes that control inflammation in both infection and sterile injury. Aberrant inflammasome activation is a driver of many diseases including: cryopyrin-associated periodic syndromes, Alzheimer’s disease, Parkinson’s disease, gout, type 2 diabetes, atherosclerosis, non-alcoholic fatty liver disease, asthma, and silicosis. Targeted inflammasome blockade is thus a promising therapeutic strategy. Most of our understanding of inflammasome function is derived from mouse studies, thus how inflammasomes are regulated in humans is currently incompletely understood.

This project will examine inflammasome regulation, specifically in human cells, by using human induced pluripotent stem cells (hiSPCs) to generate macrophage cell models. Using CRISPR/Cas9-mediated gene editing of hiPSCs, we will interrogate how primate lineage-specific CARD-only proteins and Pyrin-only proteins regulate inflammasomes in human macrophages. It is increasingly appreciated that post-translational modifications (PTM) of inflammasome components are important regulatory checkpoints. We will examine how PTM of the inflammasome sensor NLRP3 control its activation, and dictate cellular responses including cell death and cytokine secretion. Characterising these regulatory mechanisms in a novel human cell system will enhance our understanding of the pathological role of inflammasomes and will generate novel targets for therapeutic intervention.

This project will be based at the internationally renowned Wellcome-Wolfson Institute for Experimental Medicine. The WWIEM is a hub for world-class researchers, experts in the fields of immunology, microbiology, molecular and cell biology, and clinical trials. In a highly collaborative environment, our collective focus is to understand why patients develop diseases and to make the discoveries which will lead to new therapies and improvements in their quality of life.
 
Key References:

1. Broz, P. & Dixit, V. M.
Inflammasomes: mechanism of assembly, regulation and signalling.
Nat Rev Immunol 16, 407-420, doi:10.1038/nri.2016.58 (2016).

2. Coll, R. C. et al.
A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases.
Nat Med 21, 248-255, doi:10.1038/nm.3806 (2015).

3. Indramohan, M., Stehlik, C. & Dorfleutner, A.
COPs and POPs Patrol Inflammasome Activation.
J Mol Biol 430, 153-173, doi:10.1016/j.jmb.2017.10.004 (2018).

4. Bezbradica, J. S., Coll, R. C. & Schroder, K.
Sterile signals generate weaker and delayed macrophage NLRP3 inflammasome responses relative to microbial signals.
Cell Mol Immunol 14, 118-126, doi:10.1038/cmi.2016.11 (2017).

5. Lee, C. Z. W., Kozaki, T. & Ginhoux F.
Studying tissue macrophages in vitro: are iPSC-derived cells the answer?
Nat Rev Immunol 18, 716-725, doi: 10.1038/s41577-018-0054-y (2018)
 

Funding 

*FUNDING CONFIRMED – Department for the Economy (DfE)*

Eligibility for both fees (£4260 for 2018/19, 2019/20 TBC) and maintenance (£14,777 for 2018/19, 2019/20 TBC) depends on the applicants being either an ordinary UK resident or those EU residents who have lived permanently in the UK for the 3 years immediately preceding the start of the studentship.

Non UK residents who hold EU residency may also apply but if successful may receive fees only.

For further details re eligibility criteria (including academic, citizenship and residency criteria) please click on the following link: View Website

Entry Requirements 

Candidates should have or expect to obtain a 2:1 or higher Honours degree or equivalent in a relevant biomedical or life sciences subject. 


ENGLISH LANGUAGE REQUIREMENTS 

Candidates should have or expect to obtain a 2:1 or higher Honours degree or equivalent in a relevant biomedical or life sciences subject.

English Language

Candidates applying from countries where the first language is not English should produce evidence of their competence through a qualification such as IELTS or TOEFL score.

The minimum recommended score for the School of Medicine, Dentistry and Biomedical Science is:
• IELTS score of 6.0 with not less than 5.5 in each of the four component elements of listening, reading, speaking and writing taken within the last 2 years;
• TOEFL score of 80+ (internet basted test), taken within the last 2 years, with minimum component scores of; Listening 17, Reading 18, Speaking 20, Writing 17);
• A valid Certificate of Proficiency in English grade A or B;
• A valid Certificate of Advanced English grade A; or
• A first or upper second class honours degree from a university based in the UK, Republic of Ireland or other suitably quality assured location in a country deemed by the UK Border Agency to be majority English speaking.

For a list of English Language qualifications also accepted by the School and University please see the following link:
http://www.qub.ac.uk/International/International-students/Applying/English-language-requirements/#English

The English Language Unit (ELU) offers both pre-sessional and in-sessional courses in English for academic purposes and study skills. Courses vary in length and full information can be obtained from the ELU http://www.qub.ac.uk/tefl/

 

Supervisors

Dr R Coll

Dr P Moynagh

Closing Date

Closing date for application is: Sunday January 20, 2019

How to Apply

Please refer to 'Entry Requirements' for specific admissions criteria.

Apply online via the Queen's on-line application portal .  Guidance is available on the University’s Prospective Student pages.

When applying for a project, please choose ‘MEDICINE’ as your subject area/School.

Please ensure you adhere to the closing dates.

If you have any further queries please contact:  pgoffice.smdb@qub.ac.uk  or +44 (0) 28 9097 2619/2042.

 

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