Regulation of the androgen receptor: potential effects of gender and cellular environment

Sex steroids including androgens are master regulators of cell function with well-established roles in regulation of anabolic metabolism, reproduction and cancers. The androgen testosterone (T) and its metabolite dihydrotestosterone (DHT) both act through the androgen receptor (AR).

Synthetic activators (agonists) and inhibitors (antagonists) have been developed using molecular modelling techniques. Androgens are ‘Goldilocks factors’ with either too little, or too much, having an adverse effect on normal tissue function.

To address excess androgen action AR antagonists are used clinically in the treatment of polycystic ovarian syndrome, hirsutism and prostate cancer. Conversely androgen replacement has benefits for men with low testosterone due to testicular defects (hypogonadism) and may also have more general health benefits for ageing men and women in terms of maintaining muscle and bone integrity and cardiovascular health although this is controversial.

As AR acts as the gatekeeper for androgen action it is essential we gain a full understanding of the molecular systems responsible for controlling its expression and activation in diverse tissues. We have recently identified and characterised a novel binding site for the AR within its own gene, that mediates down-regulation of receptor expression, as well as crucial roles for positive (Sp1) and negative (Pur-α) regulatory proteins.

Our studies in primary human endometrial cells have demonstrated key impacts of AR agonists including selective androgen receptor modulators (SARMs) on cell function and we have developed innovative 3D model culture systems. We are therefore uniquely positioned to investigate and compare the molecular basis for regulation of the AR mRNA and protein in male (prostate) and female (endometrium, breast) tissues.

Specific Research Questions and Objectives

1.To measure, and compare, the expression of the AR gene mRNA and protein in key target tissues in response to hormone and drugs which target the receptor (i.e. SARMs) or the transcription factor Sp1 (Mithramycin A).
2.To determine the mechanism of AR-auto-repression at a primate specific ARE located in the 5’ UTR of the human receptor gene in prostate, breast and endometrium epithelial cells.
3.To measure the transcription of the AR gene in a physiological relevant cell models (i.e. co-culturing of stromal and epithelial cells) and determine the basis and consequences of potential differential regulation of the receptor in these different cell types.
4.To refine and test a mathematical model based on parameters generated from our ‘wet’ experiments in different cell-types, in order to develop a predictive tool for potential gender selective regulation of receptor levels.

Research Training:

The student will receive extensive training in cell biology and endocrinology as well as in advanced molecular methodologies specific to the project. They will learn about the fundamentals of mathematical modelling and apply them to aspects relevant to the project under the guidance of Dr Ullner. A strong emphasis will be placed on training in experimental design, data collection and data analysis including statistics.

The student will also benefit from the dynamic research environments offered by the Institute of Medical Sciences (Aberdeen) and the Centre for Inflammatory Research (Edinburgh) as well as the exciting range of molecular, cellular and in vivo models that have been developed by the Saunders and McEwan laboratories.

The student will participate in the Seminar programmes at both Institutions (location depending upon their programme of work) and the student/post-doctoral journal club. The Graduate School (College of Life Sciences and Medicine, Aberdeen) and several other sections of the university offer training sessions to allow the graduate student the opportunity to acquire and develop personal and transferable generic skills. For example, the Researcher Development Unit supports personal, professional and career development and offers a range of activities designed to help the student maximise their learning opportunities at Aberdeen and to provide a skills base for future career development.

The supervisory team have both national and international reputations in the areas of androgen signalling in male and female reproductive tissues and steroid receptor structure and biology and mathematical modelling of biological systems. This together with the collaboration links already existing between the lead supervisor and both the other members of the team makes them well placed to support the proposed project goals and training objectives.