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PROJECT TITLE

Exploring endometrial cellular heterogeneity and its role in endometriosis using single-cell transcriptomics

SUPERVISORS

Prof Christian Becker
Dr Nilufer Rahmioglu
Prof Krina Zondervan 

DESCRIPTION OF PROJECT

This outline describes our endometrial biology research programme within the Endometriosis CaRe centre (Nuffield Dept of Obstetrics & Gynaecology) and the Wellcome Trust Centre for Human Genetics, and opportunities for DPhil/MSc projects therein. The programme connects directly with laboratory-based and clinical translational programmes offered within the Endometriosis CaRe centre.

Our group focusses on understanding the biology and underlying mechanisms of a variety of reproductive diseases such as endometriosis, uterine fibroids and related women’s health conditions through the integration of large-scale genomic, molecular and environmental epidemiological approaches. Endometriosis is a chronic inflammatory disease in which tissue resembling endometrium (the lining of the womb) is located outside the womb. It causes debilitating pelvic pain and reduced fertility, and affects 1.5 million women in the UK and 176 million worldwide. Endometriosis is estimated to cost the UK economy £8.2 billion a year in healthcare and loss of work. The condition represents a significant clinical and societal health problem for which new methods of diagnosis and treatment are urgently needed. This can only be achieved by improved understanding of the underlying disease processes.

Family studies show genetic factors contribute substantially to endometriosis risk. Professor Zondervan leads a global consortium that has identified most of the genetic variants associated with endometriosis known to date. However, translation of these results into new treatment targets or biomarkers requires investigation of their effects on biological pathways in disease-relevant tissue: the endometrium. No such data currently exist. Endometrium mainly consists of two types of epithelial cells surrounded by stromal cells. Understanding the role of individual cells in disease mechanisms requires the ability to conduct such studies at the single cell level. Single-cell expression profiling (RNA-sequencing) is an important new method that allows the study of gene expression signatures of hundreds of individual cells. Its technological implementation was recently funded through a substantial strategic investment at Oxford (Oxford Consortium for Single Cell Biology-OCSCB).

The Oxford Endometriosis CaRe Centre (Co-Directors: Becker and Zondervan) is a world leader in endometriosis research. In 2012, we established ENDOX, a prospective study to collect biological samples, including endometrial biopsies, in women undergoing surgery for suspected endometriosis. We lead an international programme that produced standardised clinical and epidemiological data collection and standard operation procedures for sample collection, which will enable further large-scale collaborations in the field (endometriosisfoundation.org/ephect). Over the past years we developed expertise in detection, separation and processing of endometrial cell types. We conducted a proof-of-methods study of single cell RNA sequencing of healthy endometrium to investigate the impact of different isolation methods and dissect cell-type specific gene expression profiles. This highly novel project in collaboration with OCSCB will provide the first data on endometrial single-cell characterisation and functionality.

There are a number of potential DPhil projects available within the group, which would be tailored to a candidate’s preferences. These can include investigation of cell type specific roles in:

• Normal endometrial function and cyclical tissue transformation;
• Endometriosis pathogenesis, including translation of genetic findings;
• Endometrial involvement in reproductive biology in general;
• Other endometrial disorders including endometrial cancer;
• Identification of rare cell populations within the endometrium, such as endometrial stem cells or tissue resident/stromal immune cells;

 

TRAINING OPPORTUNITIES

We are a multi-disciplinary, dynamic group based at both the Endometriosis CaRe Centre (Nuffield Dept of Obstetrics & Gynaecology) and the Wellcome Trust Centre for Human Genetics (WTCHG) with strong links to other centres locally (e.g. Oxford Consortium for Single Cell Biology). Students will benefit from an exciting combination of clinical and basic research environments offered by both. The Endometriosis CaRe centre focuses on the integration of clinical diagnosis, care and treatment of the disease with clinical and basic research. At WTCHG, we are part of the Genetic and Genomic Epidemiology Unit (GGEU), with strong connections to Big Data Institute and Target Discovery Instutute groups in Oxford. Students will be strongly encouraged to publish their work, present at international conferences, attend bi-weekly GGEU meetings, journal clubs, as well as departmental seminars and training courses.

Above projects will be utilizing a broad spectrum of molecular biology methods including primary endometrial cell cultures, high-throughput sequencing (targeted, exome, whole genome, single cell transcriptomics) and flow-cytometry. Students will have the opportunity to gain knowledge and experience of state-of the-art computational, statistical, and technological methodologies for the generation and analysis of large-scale genomic data. The group benefits from a strong international network of collaborators in the fields of endometriosis, statistical genetics, genomics, bioinformatics, and functional biology locally, with whom students will be able to collaborate (e.g. Harvard Medical School, Boston,US; University of Michigan, Grand Rapids, US; Queensland Institute of Technology, Brisbane, Australia; Baylor College of Medicine, Houston, USA; University of Madison-Wisconsin, Madison, US; University of Tartu, Estonia).

FUNDING INFORMATION

We invite both funded and unfunded applicants, though we currently do not have funded DPhil projects in place. For eligible applicants without secured funding we are happy to advise on the potential (competitive) scholarship routes available.