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Neuroendocrine cells act as an interface between the nervous and endocrine systems, releasing hormones into the blood as a result of neuronal signals. Tumours arising in these cells are designated neuroendocrine tumours (NETs). NETs can be benign or malignant and occur in multiple organs including the pituitary (Thakker, et al. 2012).

Pituitary tumours are common and represent the most frequently encountered intracranial tumours, with the majority (>65%) secreting excessive hormones (e.g. prolactin, growth hormone, adrenocorticotropic hormone, and thyroid stimulating hormone) that result in specific endocrine symptoms e.g. excessive growth, and are referred to as functional. The remaining ~35% do not secrete hormones (called non-functioning), meaning they escape early detection, and can therefore be much larger at diagnosis and may cause e.g. vision defects. Pituitary tumours occur as part of a hereditary (i.e. familial) disorder, or as non-familial (i.e. sporadic) disease (Yates, et al. 2014), however despite a number of causative genes being identified, including MEN1 and AIP, the genetic mechanisms underlying the causes for the majority (>60%) of pituitary tumours remain to be elucidated

Our group has previously performed whole exome sequencing on multiple individuals with non-functioning pituitary tumours (Newey, et al. 2013), however this did not identify a key gene involved in driving pituitary tumour development. The analysis has therefore been extended to performing whole genome sequencing on multiple individuals, as well as families with pituitary tumours, to identify novel genetic mutations that may be causing pituitary tumour development. This analysis has identified over 400 candidate genes with mutations.

The objective of this DPhil project is therefore to select and characterise the function of the identified mutations from our whole genome sequencing, and determine the mechanisms by which they may contribute to tumourigenesis. The student will assess the effects of the mutation both in vitro using cell lines, and by developing in vivo models, using methods similar to those previously described (Gorvin, et al. 2014; Lines, et al. 2016; Newey et al. 2013), with the aim of gaining greater insight into the genes and pathways involved in pituitary tumourigenesis, which is important for correct diagnosis and treatment. 

Training Opportunities

The project would be based at the Oxford Centre for Diabetes, Endocrinology and Metabolism. This DPhil would provide training in a wide range of basic molecular biology techniques including DNA sequencing, Western Blot, PCR and immunohistochemistry; cellular biology techniques including cell culture, cell transfections, proliferation assays, apoptosis assays, flow cytometry analysis and microscopy; as well as the use of in vivo models. The successful applicant will be co-supervised by Dr Kate Lines and Dr Mark Stevenson, postdoctoral research assistants within the group with experience in the above-mentioned techniques. 

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

The department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.

Publications

1

Gorvin CM, Newey PJ & Thakker RV 2014 Functional evaluation of rare genetic variants in the prolactin receptor. Endocrine reviews 35 OR35-31.

2

Lines KE, Stevenson M & Thakker RV 2016 Animal models of pituitary neoplasia. Mol Cell Endocrinol 421 68-81.

3

Newey PJ, Nesbit MA, Rimmer AJ, Head RA, Gorvin CM, Attar M, Gregory L, Wass JA, Buck D, Karavitaki N, et al. 2013 Whole-exome sequencing studies of nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 98 E796-800.

4

Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F & Brandi ML 2012 Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 97 2990-3011.

5

Yates CJ, Lines KE & Thakker RV 2014 Molecular genetic advances in pituitary tumour development. Expert Review of Endocrinology & Metabolism.

Research Themes, Tools and Technologies

Supervisors

Key Dates for October 2018 Entry

Application deadline:  12 noon GMT on Monday 8 January 2018

Interviews for shortlisted candidates: Week commencing Monday 22 January 

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How to apply

To apply for a place on the DPhil in Medical Sciences you will need to submit an application using the online application form.

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