Mechanisms underlying the effects of rare non-coding genetic variants on vascular endothelium functions - PhD in Medical Studies (Research England DTP)

Due to a major recent award, applications are invited from students wishing to further their scientific careers by undertaking a PhD in a diabetes related area of research. Up to nine studentships will be fully funded from autumn 2020 with enhanced stipends funded from a new £6million award. This award reflects Exeter as a world renowned centre of excellence for diabetes research.

Students can select from any of the three advertised projects. These projects have been carefully selected to provide students with an excellent scientific training in an important area of diabetes research, the latest laboratory and computing skills, outstanding resources, and with world leading scientists as supervisors. They cover various aspects of diabetes research, including autoimmunity in the pancreas; neuro-endocrinology to understand the relationship between the brain, mental health and the endocrine system; gene regulation in the placenta and fetal development of the pancreas; rare genetic forms of diabetes; muscle physiology; and the use of electronic medical records to understand disease causes, treatments and progression. Students will learn a wide range of state-of-the-art techniques, which could include CRISPR-Cas9 gene editing, DNA methylation, DNA sequence analysis, muscle insulin sensitivity physiology, brain electrophysiology, medical statistics, R for statistics and data visualisation and programming in python, data science including machine learning, in vivo metabolic phenotype skills and cell biology including 3D stem cell culture. Students will have access to outstanding resources, including cohorts of >5000 patients with rare defects in insulin secretion, a world leading collection of samples for study of pancreas pathology, resources of electronic medical records and biobanks from millions of people and unique resources for studying human development of the pancreas and brain.

Project Description:

The growing number of whole genome sequencing data has revealed thousands of rare genetic variants; however, it is not always straightforward to determine which of these variants play a role in any of the pathologies affecting an individual, because the vast majority of the genetic variation occurs outside the coding sequence of a gene.

To prioritise the search of causal variants, we have characterised the genome non-coding space in cells playing a role in cardiovascular disease and thrombosis, to identify elements with regulatory functions: transcriptional enhancers, open chromatin and DNA long range interactions.

The student will use genome editing (CRISPR/Cas9) to generate induced pluripotent stem cells (iPSC) harbouring the genetic variants found in patients, or other forms of CRISPR/Cas9 to modulate the expression of the gene/s targeted by the regulatory element of interest. Engineered iPSC will be differentiated in endothelial cells, using a well-established protocol, and subjected to different functional assays to determine which functions are affected and how these changes influences disease pathophysiology.

Genetic variants have already been selected and you will be participating in the shortlisting. iPSC techniques, genome editing and functional assays are already available in the laboratory.

You will have access to an extremely data rich environment and will become familiar with data analysis, next generation sequencing data, and statistics; as well as several leading-edge laboratory techniques.