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(MRC DTP) A single cell genomics approach to predicting treatment response in juvenile idiopathic arthritis


Project Description

Juvenile idiopathic arthritis (JIA) is a group of chronic arthropathies of unknown cause affecting children under 16yrs, and is the most common childhood inflammatory rheumatic diagnosis, affecting 1 in 1,000 UK children. Using the International League against Rheumatism (ILAR) classification criteria [1], the disease can be stratified into seven distinct subtypes, a shared characteristic of which is chronic joint inflammation, resulting in pain, joint dysfunction and where uncontrolled, long-term disability. It is now well established that early, effective treatment correlates with best long-term outcomes [2,3]; therefore the first few months represent an extremely important window in which to administer effective therapy, especially in a disease where onset of disability can progress rapidly.

There are various treatment options available to manage the disease, however, response to a given drug is not universal and up to 50% of patients will not respond satisfactorily to treatment, necessitating a change in therapeutic regime. In the time it takes to find an effective treatment, the disease can continue to progress and can result in increased pain, unnecessary risk of suffering from adverse events and a significantly reduced quality of life. Uncertainty around whether or not a drug will work, and the likelihood of side-effects is a significant source of stress for patients and their families at an already difficult time. However, it is not yet possible to identify those patients who will/will not respond to treatment before it is given. It is extremely important from both the patient and the economic perspective that the level of uncertainty around likely response to treatment is reduced and that the first drug given to a patient is chosen because it is likely to be effective

Identification of cellular signatures may help us to identify mechanisms of disease/treatment response. Previous studies have focused on analysing cells in bulk where differences between individual disease associated cells may be masked. For example, only a small proportion of cells may be driving response/resistance to a particular treatment. Single cell genomics are powerful methods offering the ability to explore disease mechanisms and treatment response within individual cells and are therefore not confounded by cellular heterogeneity; thus they potentially play a key role in implementing personalised medicine initiatives. Towards this end, we propose to use single cell methodologies to identify cell subsets and biomarkers indicative of treatment response in JIA.

http://www.cfgg.manchester.ac.uk
https://www.clusterconsortium.org.uk/

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, He X, Maldonado-Cocco J, Orozco-Alcala J, Prieur AM et al.: International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004, 31:390-392.
2. Wallace CA, Ringold S, Bohnsack J, Spalding SJ, Brunner HI, Milojevic D, Schanberg LE, Higgins GC, O'Neil KM, Gottlieb BS et al.: Extension study of participants from the trial of early aggressive therapy in juvenile idiopathic arthritis. J Rheumatol 2014, 41:2459-2465.
3. Wallace CA, Giannini EH, Spalding SJ, Hashkes PJ, O'Neil KM, Zeft AS, Szer IS, Ringold S, Brunner HI, Schanberg LE et al.: Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis Rheum 2012, 64:2012-2021.

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