About the Project
Number of awards:
1
Start date and duration:
October/November 2020 (flexibility can be accommodated) for a three year PhD.
Overview:
This study will investigate the molecular pathology of GvHD, by further understanding circulatory microRNA profiles in the extracellular vesicles of patient serum. Studies will focus on patients undergoing ECP therapy, which has been shown to have significant success, despite the precise mechanisms of action being unknown. As well as inform on the molecular pathogenesis of GvHD, this will provide novel insights into mechanisms to intervene disease pathology via ECP therapy, leading to earlier and more successful intervention.
Background:
Despite allogeneic haematopoietic stem cell transplantation (allo-HSCT) being a curative treatment for haematological malignancies, graft-versus-host disease (GvHD) is a major complication, and severe disease is associated with 40-60% mortality. The pathology of GvHD has been generally attributed to three main stages, however, the detailed molecular pathology is poorly understood, particularly in the chronic and steroid-resistant forms. Further understanding of this complex and systemic disease is urgently needed.
Extra corporeal photopheresis (ECP) therapy is successfully used in the treatment of non-responding GvHD, particularly steroid-resistant disease. However, the mechanisms of ECP action are not completely understood, particularly as it is frequently used in cases with complex pathophysiology. Some studies have shown that ECP can induce a Th1 to Th2 immune response shift in GvHD patients, resulting in decreased inflammatory cytokines, increased anti-inflammatory cytokines and the proliferation of regulatory cells, including Tregs. However, evidence also suggests that the ECP mechanism relies on recruitment and involvement of additional immune cells.
MicroRNAs have been shown to target key pathways implicated in the pathology of GvHD, and interestingly they can be found within biofluids, where they are actively packaged into extracellular vesicles (EVs). The immunoregulatory activities of EVs are wide ranging, and evidence suggests their involvement in Treg and Th1/Th2 responses.
The aim of this project is to investigate circulatory EV microRNAs post-HSCT and in GvHD patients receiving ECP therapy. As ECP is safe to administer with few significant adverse effects, it has the potential for earlier use in the post-HSCT treatment of GvHD. Thus, further understanding the molecular mechanisms of ECP action, including EV microRNAs, may justify more timely use of ECP in clinical practice, as well as identify molecular targets that may be implicated in disease pathogenesis, and biomarkers for using ECP as first line or pre-emptive GvHD therapy.
Also see https://www.ncl.ac.uk/postgraduate/funding/sources/allstudents/tc011.html
Sponsor:
The Pathological Society of Great Britain and Ireland.
Name of supervisor(s):
Professor Matthew Collin (https://bit.ly/3fOiLl0), Professor Andrew Gennery (https://bit.ly/30LKOgv), Dr Rachel E Crossland (https://bit.ly/3iwllOd)
Eligibility Criteria:
You must have, or expect to achieve, at least a 2:1 Honours degree or international equivalent, in a subject relating to molecular biology, immunology or transplantation sciences, but other subjects considered. A further qualification such as an MRes or other research experience is advantageous.
This award is available to UK/EU and international applicants.
To study this course you need to meet the following English Language requirements: IELTS 6.5 overall (with a minimum of 5.5 in all other sub-skills).
How to apply:
You must apply through the University’s online postgraduate application system by creating an account. To do this please select ‘How to Apply’ and choose the ‘Apply now’ button (https://bit.ly/3kymCGn).
All relevant fields should be completed, but fields marked with a red asterisk must to be completed. The following information will help us to process your application. You will need to:
click on programme of study and insert 8300F in the programme code section
select Programme name ‘PhD in the Faculty of Medical Sciences (full time)’
insert the studentship code TC011 in the studentship/partnership reference field
attach a covering letter and CV. The covering letter must state the title of the studentship, quote reference code TC011 and state how your interests and experience relate to the project
attach degree transcripts* and certificates and, if English is not your first language, a copy of your English language qualification.
*You will not be able to submit your application until you have submitted your degree transcript/s.
Please also send your covering letter and CV to [Email Address Removed].
Contact:
For further details, please email Dr Rachel Crossland, Translational and Clinical Research Institute
Telephone: +44 (0) 191 282 0451
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