(MRC DTP) Functional dissection of disease associated genetic loci in rheumatoid arthritis
Dr G Orozco
Dr S Eyre
Prof A Barton
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
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.
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.
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 www.manchester.ac.uk/mrcdtpstudentships
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