Female sex steroid hormone regulation of uterine epithelial cell proliferation and differentiation for embryo implantation

3-Year PhD Studentship in Reproductive Health Sciences

Supervisor - Jeffrey W. Pollard, Director, MRC Centre for Reproductive Health.

Project - Female sex steroid hormone regulation of uterine epithelial cell proliferation and differentiation for embryo implantation

The Medical Research Council (MRC) Centre for Reproductive Health (MRC-CRH) conducts research into conditions that affect reproductive fitness and the health of male and female reproductive organs including infertility, endometriosis and premature birth. The Centre brings together scientists who have outstanding strengths in reproductive biology, stem cells, inflammation, development, hormonal disease and imaging. We provide a rich environment for training of clinical and non-clinical scientists and a vibrant programme of activities aimed at encouraging public engagement in science.

Three 3-year PhD Studentships will be available in September 2013 to outstanding science graduates wishing to pursue a career in Reproductive Health Sciences. The studentship will cover tuition fees at the UK/EU rate, a stipend (currently £13,726) with a rise each year to match inflation. This PhD Programme seeks to attract the best students from across the UK and EU to join our internationally recognised research community of Reproductive Health Scientists in Edinburgh. The Centre has a thriving postgraduate community of more than 30 MSc and PhD trainees who are mentored by a postgraduate studies committee.

Applicants are expected to have a good honours degree in the sciences (biological, chemical or physical), at least UK level of 2.1 or the equivalent from non-UK universities. A Master’s degree in relevant subject would be an advantage.

The Little France Campus

The Centre for Reproductive Health is located on the ground floor of the Queen’s Medical Research Institute on the University of Edinburgh’s Medical Campus at Little France. (http://www.ed.ac.uk/schools-departments/medicine-vet-medicine/about/little-france) The CRH enjoys close collaborative links with the other Centres on the Little France Campus including the MRC Centre for Inflammation Research (MRC-CIR); the British Heart Foundation Centre of Excellence in Cardiovascular Science (BHF-CVS) and the Clinical Research Imaging Centre (CRIC) and the MRC Centre for Regenerative Medicine (CRM).

The female sex steroid hormones, estradiol (E2) and progesterone (P4), control female fertility through their action in the uterus. In both mice and humans E2 induces luminal and glandular cell proliferation. P4 acts antagonistically blocking this estrogen stimulated cell proliferation and causing differentiation of the epithelium into a state receptive for embryo implantation. These actions can be mimicked in ovariectomized mice by exogenous hormone administration thereby making this an ideal system in which to study the biology of a simple epithelium and the control of cell division in mammals.

Our previous studies have identified several pathways involved in the regulation of DNA synthesis that are stimulated by E2 and inhibited by P4 and that are mediated by their transcription factors receptors, ER and PR, respectively. Importantly we discovered transcription factors that act downstream of the steroid hormone receptors and that act in a cell autonomous fashion. Chief among these are members of the Kruppel like family (KLF) and in particular, KLF4 and KLF15, that acts downstream of the ER and PR respectively. The proposed Ph.D. project is to further characterize the molecular basis of the action of these KLFs. The specific aims are:

1. Identify transcriptional targets of KLF4 and 15 in the uterus and determine functions of key genes in cell proliferation and implantation
This aim will use ChIPseq on a genome wide scale to identify transcriptional targets followed by validation of transcriptional regulation using conventional assays. Gene ablation in vivo will be used to determine the function in cell division and implantation of uniquely identified target proteins.

2. Analyze the function and redundancy between different members of the KLF transcriptional family.
Gene ablation of KLF15 causes sub-fertility attributed to the maintenance of a hyper-estrogenic phenotype in the face of P4 treatment. Using ChIP we have determine at the molecular level that KLF5 binds to DNA binding sites previously occupied by KLF15 suggesting compensation. The project will generate compound mutant mice and determine the phenotype and functional consequences of loss of both KLF5 and 15 genes. In addition, conditional genetic approaches will be developed to ablate KLF 4 specifically in the uterine epithelium to determine its function in E2 action and fertility.

Proliferative disorders of the endometrium ranging for endometrial cancer to endometriosis are a significant health issue for women. In addition exposure to estrogen is a major risk factor for endometrial and breast cancer. The molecular bases of these disorders and for estrogen sensitivity are unknown. This project aims to provide mechanistic insight into the action of female sex steroid hormones in regulating cell proliferation and suggest potential therapeutic opportunities to treat these diseases.

How to Apply

For application, please submit a copy of:
• A curriculum vitae
• A ‘statement of purpose’ outlining your reasons for undertaking this programme of study and how you see it affecting your career plan, together with an indication of which project you are interested in (see list below)
• 3 academic references should email/send letters on your behalf to: [Email Address Removed]

PLEASE NOTE Applications sent directly to project supervisors may not be counted.

The closing date to apply for these studentships is Monday 11 March 2013.

If you have any questions regarding the programme please contact the programme secretary [Email Address Removed]