Polycystic ovary syndrome (PCOS) is a condition that affects >5% of women of reproductive age and is the most common cause of menstrual dysfunction and is associated with metabolic abnormalities and increased risk to long-term health. It is generally accepted that PCOS is a genetically determined, primary ovarian disorder, where the clinical symptoms occur as a consequence of excess androgen production at or before puberty. Androgens play a key role as substrate for estrogen synthesis in the ovary – however, ourselves and others have also shown that androgens have a growth promoting effect on preantral follicles; this is important, because it suggests that high levels of androgen may change the normal course of follicle development – potentially leading to a perturbed ovarian phenotype.
In order to further understand the molecular basis of the effect of androgens on preantral follicle development, we recently carried out an RNA-seq analysis of isolated mouse preantral follicles under different androgen conditions. From that study we identified a number of androgen-responsive genes in preantral follicles that are also associated with gene ontology terms such as ‘abnormal ovarian morphology’ and ‘abnormal ovulation’ – therefore, one of the aims of this project will be to focus on some of these candidates to determine their role in precipitating dysregulated follicle development. The RNA-seq study also showed that elevated androgens led to an increase in expression of a suite of androgen biosynthesis enzymes - thus conceivably creating a self-propagating mechanism of androgen hypersecretion. A second aim of this project proposal will be to identify the specific cells that are producing these steroidogenic enzymes and to examine how this relates to the production and secretion of specific steroid hormones such as testosterone and estrogen.
This project will utilise a well-established mouse preantral follicle culture model in order to examine the aims above. We can also use this model to examine the functional knock-down of specific gene targets and pathways using siRNA and small molecule inhibitors, respectively. Outputs such as gene expression and protein expression will be examined using qPCR (mRNA), RNAScope (mRNA), ELISA (hormones), immunofluorescence (protein), combined with high-resolution imaging (e..g confocal microscopy) and morphological analyses.
Entry Requirements:
Candidates must have a first or upper second class honors degree or significant research experience. Applicants should ideally have a background in reproductive science or endocrinology.
How to apply:
Please complete a University Postgraduate Research Application form available here: www.shef.ac.uk/postgraduate/research/apply
Please clearly state the prospective main supervisor in the respective box and select School of Medicine & Population Health (Oncology and Metabolism) as the department.
Enquiries:
Interested candidates should in the first instance contact
Dr Mark Fenwick m.a.fenwick@sheffield.ac.uk
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