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Functional dissection of disease associated genetic loci in rheumatoid arthritis

   Faculty of Biology, Medicine and Health

  , ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Rheumatoid arthritis (RA) is a common chronic inflammatory disease characterized by inflammation of the joints and has a high socioeconomic burden.

Through the application of genome wide association studies (GWAS), over 100 genetic variants have been associated with RA risk. 90% of them lie outside protein coding genes and, therefore, their potential role in pathological mechanisms is not obvious, but there is now strong evidence that disease associated non-coding variants are involved in transcriptional regulation.

The aim of the project is to characterize regulatory elements harbouring RA-associated variants, in order to determine the genes, biological pathways and mechanisms by which these variants act in specific cell subtypes to increase the risk of disease, with the following specific objectives:

1. To identify the genes that cause RA: we will map cis-regulatory chromatin contacts in immune cells from RA patients that have high disease activity and that are in remission, as well as in healthy individuals in a high throughput manner (Hi-C) in multiple biological replicates. For these biological samples, we will also characterize active regulatory elements (enhancers) using ChIP-Seq. These experiments will allow us to identify disease-specific enhancer-promoter interactions that will define relevant genes in the pathology of RA. By overlaying the GWAS data, active enhancers affected by disease-associated variants will also be defined.

2. To investigate the effect of RA associated variants on the regulation of transcription: Since the dysregulation of gene expression is a major contributor to complex diseases like RA, transcriptomic profiling can also help us identify the genes that are important in disease. We will perform RNA-Seq in RA patients and healthy individuals, which will allow us to detect differentially expressed genes between these groups. We will also explore whether RA-associated SNP genotypes are correlated with differential gene expression in both RA patients and healthy individuals.

3. Validation of function of disease SNPs on gene expression: The genetics and genomic data generated in objectives 1 and 2 will be used to prioritise causal genes at RA susceptibility loci. We will use the genome editing technology CRISPR/Cas9 to verify target genes and the functional importance of identified elements containing RA associated variants for selected loci.

This project will therefore contribute to the identification of fundamental genes and biological pathways that mediate RA pathology, which will in turn inform novel therapeutic targets discovery and drug repurposing.



Entry Requirements

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area/subject. Candidates with previous laboratory experience are particularly encouraged to apply.

How To Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the appropriate subject title.

For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences.

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/”

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website View Website

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