Download (CF): identifying therapeutic targets

PhD Studentship in the Leeds Institute of Rheumatic
and Musculoskeletal Medicine (LIRMM)
Faculty of Medicine and Health
University of Leeds
The unfolded protein response, defective autophagy and inflammasome activation in
cystic fibrosis (CF): identifying therapeutic targets in CF-related joint disease
(arthropathy).
Supervisors: Professor Michael McDermott, Professor Daniel Peckham, Dr Sinisa
Savic
Funding: Leeds Institute of Biomedical & Clinical Sciences Cystic Fibrosis
Studentship
A PhD studentship is available for UK and EU citizens only. The studentship will attract an
annual tax-free stipend of £14,296 for up to 3 years, subject to satisfactory progress and will
cover the UK/EU tuition fees. This project is for an immediate start, however there is
flexibility for the most suitable candidate.
You should hold a first degree equivalent to at least a UK upper second class honours
degree in a relevant subject. This project would suit a student with a strong background in
immunology and training in molecular biology. Laboratory training will also be provided.
Candidate whose first language is not English must provide evidence that their English
language is sufficient to meet the specific demands of their study, the Faculty minimum
requirements are:
•
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British Council IELTS - score of 6.5 overall, with no element less than 6.0
TOEFL iBT - overall score of 92 with the listening and reading element no less than
21, writing element no less than 22 and the speaking element no less than 23.
Research Project:
Cystic Fibrosis (CF), the most common genetic condition in the UK, is caused by mutations
in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF is a
multisystem disease characterized by chronic bronchial infection and progressive lung
disease, but it may affect most organs; recent data from the Leeds indicate that >20% of
patients have a history of CF associated arthritis (CFAA)(1). A form of intracellular stress,
known as the unfolded protein response (UPR), is activated in CF patients by the associated
bacterial infections (2). We have shown that this UPR causes activation of a large
intracellular protein complex, the NLRP3 inflammasome, which senses danger-associated
molecular pathogens (DAMPs) and is crucial for the production of pro-inflammatory
cytokines, IL-1β and IL-18.
In this multidisciplinary study we propose study the expression of a range of UPR genes in
blood, bronchial and joint (synovial) cells of CF patients, using real-time PCR analyses and
custom-made gene expression cards. In addition, we will employ complementary cell biology
techniques, including flow-cytometry, immunohistochemistry and intracellular staining, in
addition to chromatin immunoprecipitation (ChIP) assays. We will fully characterise the
molecular mechanisms underlying lung and joint disease in patients with CF, and determine
the roles of the UPR, defective autophagy and inflammasome(s) activation in their disease
(3). These studies will therefore further develop our understanding and hence improved
therapy of CFAA, by validating new targets for future therapy. The applicant will have
significant experience in some of these methodologies. A Master’s degree in a relevant area
of study is desirable but not essential.
The project will be co-supervised by Professor Michael McDermott, Dr. Daniel Peckham and
Dr. Sinisa Savic, in the Wellcome Trust Brenner Building at St. James’s University Hospital
site. These projects will be carried out in collaboration with Professor Fabio Martinon,
University of Lausanne, Switzerland. Prof. Martinon will host the PhD, in 2018-2019, which
will require the student to travel to his laboratory in Lausanne, for short periods of time.
References:
1. Peckham D, et al. (2012). J Cyst Fibros. 13:681-6
2. Ribeiro CM, et al. (2010). Proc Am Thorac Soc. 7:387-94
3. Iannitti RG, et al. (2016). Nat Commun. 14;7:10791
Environment:
The student will be based in the Leeds Institute of Rheumatic and Musculoskeletal Medicine
(LIRMM), and the Leeds Institute of Biomedical and Clinical Sciences (LIBACS), University
of Leeds. Training will be provided in the relevant technical areas. The student will become
part of a team funded by the Cystic Fibrosis Trust to work on identifying therapeutic targets
in CF arthropathy, by investigating the unfolded protein response (UPR) and disease
mechanisms in patients with CF and CF arthropathy (CFA). This project will focus primarily
on the roles of autophagy and apoptosis in CF but will also link in with other projects on the
UPR and inflammasome activation. Preliminary data from this study will be used in design of
a therapeutic trial of anti-IL-1 (anakinra/canakinumab) in CF and CFA. For informal enquiries
please contact Prof. Michael McDermott tel + 44(0)113 3438641 [email protected]
How to apply:
To apply for this scholarship applicants should complete a Faculty Scholarship Application
form and send this alongside a full academic CV, degree transcripts (or marks so far if still
studying) and degree certificates to the Faculty Graduate School [email protected]
We also require 2 academic references to support your application. Please ask your referees
to send these references on your behalf, directly to [email protected] by no later than
Monday 13 March 2017
If you have already applied for other scholarships using the Faculty Scholarship Application
form you do not need to complete this form again. Instead you should email
[email protected] to inform us you would like to be considered for this scholarship project.
Any queries regarding the application process should be directed to [email protected]
Closing date for this studentship is Monday 13 March