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Understanding common genomic pathways between endometriosis and other chronic pain conditions and their functional significance


About This PhD Project

Project Description

Lead supervisor: Prof Katy Vincent, Nuffield Department of Women’s and Reproductive Health, University of Oxford
Co-supervisor: Prof Krina Zondervan, Nuffield Department of Women’s and Reproductive Health, University of Oxford
Co-supervisor: Dr Nilufer Rahmioglu, Wellcome Centre for Human Genetics, University of Oxford
Commercial partner: Lilly UK, Ascot

Endometriosis is a chronic inflammatory disease affecting 1.5M UK women and costing the economy £8.2bn/year. Despite pain being the predominant symptom, pain-generating mechanisms in endometriosis are not well understood and current treatments frequently ineffective. Endometriosis has a moderate heritability (50%). In our ongoing International Endometriosis Genomics Consortium (25 datasets) we are currently mapping common variants associated with the disease and associated pain. Women with endometriosis pain have an increased risk of other chronic pain conditions. This may be because mechanisms generating pain are similar between conditions, and/or that women with inherited pain sensitivity are more likely to develop symptoms from underlying pathologies. Brain imaging literature suggests that there are many similarities in the alterations in brain structure and function seen with chronic pain despite different underlying pathologies.

The aims of this project are to:

1. Explore in available genetic datasets whether genetic polymorphisms known to be associated with pain vulnerability are over represented in endometriosis (e.g. BDNF and serotonin receptor variants)
2. Investigate genetic contributions to co-morbidity between pain conditions, and identify shared genes and pathways, using UK Biobank and other large-scale genomic data. We will focus on comparing women with endometriosis vs. inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and migraine; representing inflammatory, somatic and visceral pain conditions that are commonly comorbid.
3. Compare and contrast functional and structural brain connectivity, using UK Biobank brain imaging data.
4. Integrate the findings of the genetic and imaging analyses to explore whether shared genetic/pathway associations and brain changes are associated, suggesting causal pathways.
5. Utilize state-of-the-art laboratory techniques to understand expression patterns in relevant tissues of any target genes identified by the above analyses to be of high interest or potentially a novel therapeutic target.

A study overview can be found on this page - https://www.medsci.ox.ac.uk/study/graduateschool/mrcdtp/icase-2020/project-2-integrating-human-functional-genomics-epigenomics-and-transcriptomics-to-accelerate-drug-discovery-for-precision-medicine-in-asthma-acronym-oxmap-oxford-multiomics-asthma-project

Understanding the common mechanisms underlying pain conditions comorbid with endometriosis could allow for the repurposing of drugs already used to treat other pain conditions in women and the design of more targeted therapies based on the specific pain mechanisms rather than a standardised approach to the presenting pathology. Moreover, an understanding of which women are particularly vulnerable to the development of endometriosis-associated pain and/or comorbidities may allow preventative strategies to be developed and implemented potentially with significant impact on the burden of chronic pain in women and its associated financial cost to society.

Both academia and industry benefit from this collaboration. Of particular importance to industry is the availability of tissue for expression studies (collection is ongoing in our bioresource) and access to the disease-specific and clinical experience of the Oxford team which is not available in-house: Professor Zondervan and Dr Rahmioglu on the genomic analysis of endometriosis-specific datasets; Professor Vincent on clinical aspects of both endometriosis and chronic pain. For academia, access to state-of-the-art laboratory techniques to follow-up findings from the initial analyses is of key importance. Both parties are committed to future translational research in this field.

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