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Genetics: Genetic studies of corneal endothelial dystrophies and development of alternative treatment options


Key facts

Type of research degree
Application deadline
Ongoing deadline
Dr Manir Ali
Additional supervisors
Dr Manir Ali
<h2 class="heading hide-accessible">Summary</h2>

The cornea is the protective front part of the eye that provides most of the eyes focusing power. The endothelium is a single-cell layer on the inside of the cornea that maintains fluid balance and is required for corneal transparency. The late-onset inherited eye condition, Fuchs endothelial corneal dystrophy (FECD), which is the most common cause of corneal transplantation, affects 5% of people over 40 years old who develop blurred vision as a result of endothelial dysfunction and could lead to blindness. About 70% of cases are caused by a trinucleotide repeat expansion in the intron of TCF4, which causes RNA nuclear foci to develop in the patient&amp;rsquo;s endothelial cells that leads to cell death. Mendelian mutations in SLC4A11, ZEB1, LOXHD1 and AGBL1 only account for at most 5% of cases leaving about 25% of cases with unidentified mutations.

<h2 class="heading hide-accessible">Full description</h2>

<p>The primary aim of this project will be to identify the cause of FECD in those cases in whom the mutations have not yet been discovered by initially selecting those with a clear family history. Whole genome sequencing (WGS) and whole exome sequencing (WES) of these cases will identify coding and non-coding variants both in the known FECD genes and in novel genes. These variants will be further studied to provide functional validation of the genetic findings but specific experiments will be determined by the initial findings. Better understanding of the disease mechanisms in light of the molecular diagnosis will support the development of new therapies for this condition.&nbsp;</p> <p>The techniques used in this PhD will include bioinformatics, analyzing WES and WGS data, PCR, Sanger sequencing, 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. The search for therapies would include a high throughput small molecule screen with functional readout where that is available.&nbsp;</p> <p><strong>In line with the bespoke nature of our International PhD Academy a modified PhD project can be proposed dependent on students interests and background.</strong></p>

<h2 class="heading">How to apply</h2>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. To apply for this project applicants should complete an <a href="">online application form</a> and submit this&nbsp;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.</p> <p>We also require 2 academic references to support your application. Please ask your referees to send these <a href="">references</a> on your behalf, directly to <a href=""></a></p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p>

<h2 class="heading heading--sm">Entry requirements</h2>

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

<h2 class="heading heading--sm">English language requirements</h2>

Applicants 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 in IELTS and TOEFL tests for PhD, MSc, MPhil, MD are: &acirc;&euro;&cent; British Council IELTS - score of 7.0 overall, with no element less than 6.5 &acirc;&euro;&cent; 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.

<h2 class="heading">Contact details</h2>

<p>Informal enquires about regarding the bespoke taught first year of the PhD programme and research projects can be made by contacting <a></a></p> <p>Enquiries regarding the application process should be directed to the Faculty of Medicine and Health Graduate School&nbsp;Office&nbsp;e: <a href="tel:0113 343 8221"></a> t: +44 (0)113 343 8221.</p>

<h3 class="heading heading--sm">Linked research areas</h3>