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MRC Precision Medicine DTP: Genome-wide, gene-specific patterns of glucocorticoid-receptor co-regulators critical for growth and skeletal development


Project Description

Background
Glucocorticoids (GCs) are a class of steroid hormones that bind and activate the intra-cellular GC receptor (GR), and regulate transcription of many genes that govern the effects of GCs. The remodeling of chromatin and regulated assembly of active transcription complexes by the GR and other transcription factors are modulated by an array of co-activators and co-repressors, collectively named co-regulators. These co-regulators bind and direct the GR to specific promoters, thereby modulating signalling and effector pathways through the regulation of gene expression. It is likely that different co-regulators can regulate different gene expression modules and physiological pathways. This concept of differential regulation forms the basis of a novel group of drugs, the selective GC receptor modulators (SGRMs), that have the potential to precisely tailor the pharmacological outcome to the medical needs of the patient (1). However, there is very little information on the specific gene modules that are activated following exposure to SGRMs (2). Our group has focused on understanding the effects of GCs on growth and skeletal development through a range of models and this has also included a study of the effects of SGRMs on skeletal development (3). Adoption of an unbiased genome-wide analysis will allow us to improve our knowledge of SGRMs as well as GC action on growth and skeletal development.

Aims
The project relies on three-way collaboration between Glasgow, Edinburgh and Karolinska Institutet. The student will perform genome-wide global analysis by RNA-seq of GC-regulated gene expression in osteoblasts and chondrocytes maintained in culture and whole bone tissue. This will also include the identification of GC receptor regulated genes specific to different SGRMs. Cells and tissue will also be obtained from on-going in vivo studies in Edinburgh and Stockholm that involve mice being exposed to GC and a novel SGRM (MTA approved). In addition, the global analysis of GC/SGRM regulated gene expression after co-regulator depletion by siRNA approaches will identify the gene sets and physiological pathways specifically regulated by each co-regulator. The project will be supported through existing work that is being undertaken as part of a MRC Clinical Training Fellowship at the Roslin Institute under the joint supervision of Ahmed and Farquharson. Tom Freeman will provide the expertise and environment for RNA-seq experiments, use of network analysis-based methods and pathway modelling, and will provide bioinformatics training to the new PhD student enabling them to perform integrative data analyses with various large-scale sequencing data (4). In summary, the PhD student will build on the existing studies to compare the genomic fingerprint that is associated with an adverse growth and bone profile following GC exposure and compare that to the fingerprint obtained following SGRM exposure.

Training outcomes
The PhD student will join a research group with a high level of interdisciplinary skills in bone and growth plate biology, genomics, bioinformatics and endocrinology. Specifically, the student will develop project specific research skills where they will become proficient in the use of cell-based and murine models to study GC actions. By the end of the studentship the student will have an advanced level of knowledge of genomic and bioinformatic analysis as well as lab expertise in cell and organ culture, in vivo models, gene silencing, real-time PCR, western blotting, and immunohistochemistry. Ongoing formal and practical training in skills and techniques will be provided by all supervisors and members of their research groups during the studentship. The student will also develop transferable research skills through courses offered by the Institute of Academic Development. The student will participate and present their data at group meetings, journal clubs, student research days and external scientific meetings.
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This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location:

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you should contact the primary supervisor prior to making your application. Additional information on the application process if available from the link above.

For more information about Precision Medicine visit:

http://www.ed.ac.uk/usher/precision-medicine

Funding Notes

Start: September 2019

Qualifications criteria: Applicants applying for a MRC DTP in Precision Medicine studentship must have obtained, or will soon obtain, a first or upper-second class UK honours degree or equivalent non-UK qualifications, in an appropriate science/technology area.

Residence criteria: The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £14,777 (RCUK rate 2018/19) for UK and EU nationals that meet all required eligibility criteria.

Full eligibility details are available: View Website

Enquiries regarding programme:

References

1. Ayroldi E, Macchiarulo A, Riccardi C. Targeting glucocorticoid side effects: selective glucocorticoid receptor modulator or glucocorticoid-induced leucine zipper? A perspective study. FASEB J. 2014;28:5055-70.
2. Wu DY, Ou CY, Chodankar R, Siegmund KD, Stallcup MR. Distinct, genome-wide, gene-specific selectivity patterns of four glucocorticoid receptor coregulators. Nucl Recept Signal. 2014;12:e002.
3. Wood CL, Soucek O, Wong SC, Zaman F, Farquharson C, Savendahl L, Ahmed SF. Animal models to explore the effects of glucocorticoids on skeletal development. J Endocrinol. 2017; 236: R69-R91
4. Livigni A, O'Hara L, Polak ME, Angus T, Wright DW, Smith LB, Freeman TC. A graphical and computational modeling platform for biological pathways. Nat Protoc. 2018;13:705-722.

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