Investigating genetic causes and transcriptional dysregulation events associated with posterior polymorphous corneal dystrophy (PPCD).

Posterior polymorphous corneal dystrophy (PPCD) is a visually-impairing genetic disease that affects the cornea. It primarily affects a specialised layer of cells lining the innermost surface of the tissue called the corneal endothelium. Patients with PPCD experience corneal swelling and clouding, and in some cases glaucoma, that can lead to impaired vision and/or blindness. Multiple genetic causes of PPCD have been identified, but many cases remain genetically unsolved. We have recently identified that non-coding mutations in OVOL2 and GRHL2 cause PPCD using whole genome sequencing, but we do not currently fully understand how they cause disease. Iridocorneal endothelial (ICE) syndrome is another disease of corneal endothelial cell dysfunction with similar clinical features to PPCD but, unlike PPCD, patients typically present with unilateral disease and no family history of the condition. The aetiology of ICE syndrome is currently unknown.

Project Aims

This project aims to identify the genetic causes of PPCD in unsolved cases, and to investigate how PPCD-associated mutations cause corneal disease using patient-derived cells as a model system. We will also investigate the potential genetic and/or viral origins of ICE syndrome, a corneal endothelial disease of unknown aetiology.

Methods

This studentship will utilise a broad range of genetic and functional genomic techniques to explore the genetic origins of PPCD and ICE syndrome including whole genome sequencing and RNA-Seq. Using donated tissue removed during planned corneal transplant surgery, new techniques established in our laboratory to grow and maintain the corneal cells will be employed, to enable the student to investigate the functional consequences of mutations and underlying molecular mechanisms of disease. This studentship offers the opportunity for the prospective student to become proficient in a broad range of cutting-edge genomic, transcriptomic, cell biology, cell culture and molecular biology techniques.

Environment: A wide range of expertise will be readily available to support the student across all aspects of the study. The position in funded by Moorfields Eye Charity and is based at UCL Institute of Ophthalmology (IoO). UCL IoO and Moorfields Eye Hospital (MEH) environment provides an unparalleled location is support ophthalmic research. It is exceptionally well equipped with laboratories and core facilities. The joint site and close association of IoO with MEH means day to day contact with clinical colleagues and access to the most extensive clinical resource in the UK which is of particular relevance to this project given the anticipated ongoing use of patient DNA and tissue samples.

Ideal person specification

• A good degree (2.1 or above; or equivalent EU/overseas degree) in a biology/biomedical subject area, and in addition ideally a MSc in a related area
• Interested in genetics, cell biology and human diseases as well as translational research
• Excellent experimental skills, preferably in molecular biology, bioinformatics and molecular and cellular biology
• Good communication skills - especially in written English
• Very strong work ethic, with the ability to think creatively and work within a team

Duties and Responsibilities

• In vitro corneal endothelial cell culture and confocal microscopy
• Bioinformatic analysis of next generation sequencing data (whole exome sequencing, whole genome sequencing and RNA-Seq)
• Work in collaboration with other researchers
• Prepare presentations, including text and images, for delivery by self and others.
• Travel for collaboration and other meetings or conferences.
• Prepare reports, and manuscripts for submission to peer-reviewed journals.
Contribute to the overall activities of the research team, department and be aware of UCL policies.

Application procedures

Application is by CV and covering letter (including motivation for applying). Informal enquiries and applications should be emailed to [Email Address Removed]
Closing Date: 27th April 2018