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(MRC DTP) Exploring the transcriptomic and chromatin landscapes of fibroblast-like synoviocytes in rheumatoid arthritis


Project Description

Genetic studies in rheumatoid arthritis (RA) have been successful in identifying regions of the genome which contribute to disease risk, but it is often unclear which genes they effect. They have therefore had limited impact on our understanding of disease and the development of new and effective treatments. Fibroblast-like synoviocytes (FLS) are an understudied, crucial cell type in the development and progression of inflammation in the joint. We have previously used molecular biology techniques to study the characteristics of these cells at the bulk population level, overlaying known genetic risk variants. However, FLS cells are a heterogeneous mix of subtly different sub-types. Single cell genomics allows us to study this cellular heterogeneity in disease samples, giving the potential to explore how FLS cell subtypes contribute to RA risk and provide insights into treatment development.
This project will utilise single cell RNA-seq (scRNA-seq) and ATAC-seq (scATAC-seq) data to explore gene regulation and cellular heterogeneity in FLS cells in response to stimulation. Samples from individuals with RA will be used to generate both scRNA-seq and scATAC-seq at multiple time points following TNF stimulation. From this, cell sub-types will be identified and gene regulatory networks specific to each sub-type will be used to identify which genes are regulated in response to stimulation. By combining this with known RA associations, genes potentially involved in RA pathogenesis will be identified. These sub-types and genes will be further explored using molecular biology techniques established within our group, including flow cytometry, mass cytometry by time of flight (CyTOF), CRISPR/Cas9 genome editing, chromosome conformation capture, ChIP-seq and RNA-seq. This project is an exciting opportunity to work with cutting edge single cell data and molecular biology techniques. It has the potential to gain insights into the role of FLS in the development and progression of RA, how an individuals’ genetics could contribute to their risk of developing RA and inform drug development.

http://www.cfgg.manchester.ac.uk/
http://www.en.rheumatologie.usz.ch/research/CER/fibroblasts-RA/Pages/default.aspx

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.

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