Genetics: Investigating the molecular basis of optic nerve degeneration in glaucoma to try and develop a personalized medicine strategy for treatment

The optic nerve is a special sensory nerve that transmits visual impulses from the retina to the brain. Primary Open Angle Glaucoma (POAG) is a chronic, progressive optic neuropathy of multifactorial origin that affects 1 in 10 elderly individuals. The condition is characterised by an elevated intraocular pressure in the eye that causes irreversible damage to the retinal ganglion cells and optic nerve and can remain undiagnosed for many years, only affecting vision when the damage is quite advanced. An early diagnosis before significant vision loss is essential for treating this preventable condition. Glaucoma shows familial aggregation with its prevalence varying among different ethnic groups indicating that genetic factors play a major role in pathogenesis. Mendelian mutations in myocilin, optineurin and WD-repeat-36 of large effect, and at least 20 genetic loci in different genes contributing small effects, only account for at most 5% of cases suggesting that the underlying genetic cause for the majority of cases remains to be discovered.

The primary aim of this project will be to identify POAG patients with defined genetic subtypes enriching for patients with a strong family history. Whole genome sequencing (WGS) and whole exome sequencing (WES) of the familial cases will identify coding and non-coding variants both in the known POAG genes, myocilin, optineurin and WD-repeat-36, and in novel genes. These variants will be further studied on neurological tissue or cells to provide functional validation of the genetic findings but specific experiments will be determined by the initial findings. In each case the better understanding of the disease mechanisms in light of the molecular diagnosis will initiate re-examination of the patients, histories compared and best treatment practise for each subgroup inferred. If successful, this approach may also support the development of new therapies for this complex condition.

The techniques used in this PhD will include PCR, Sanger sequencing, bioinformatics, analyzing WES and WGS data, functional validation of variants may include expression profiling, spicing mini- and midi-gene assays, protein structural modelling, RNA sequencing, creating knock-out cell models of putative pathogenic variants by CRISPR-Cas9 genome editing and the study of animal models where available.

This project is available as part of the International PhD Academy: Medical Research

Eligibility:

You should hold a first degree equivalent to at least a UK upper second class honours degree in a relevant subject.

Candidates whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Medicine and Health minimum requirements are:

• British Council IELTS - score of 7.0 overall, with no element less than 6.5
• TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.

How to apply:

Applications can be made at any time. To apply for this project applicants should complete an online application form and submit this alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates. Please make it clear in the research information section that you are applying for the International PhD Academy: Medical Research, as well as the title of the project you wish to be considered for.

We also require 2 academic references to support your application. Please ask your referees to send these references on your behalf, directly to [Email Address Removed]

Any queries regarding the application process should be directed to [Email Address Removed]