PhD Study : An Investigation of Mechanisms and Biomarkers of Transforming Growth Factor-beta Induced Corneal Dystrophies

Apply and key information  

Summary

Corneal clarity is a prerequisite for vision. Transforming growth factor beta-induced protein (TGFBIp) is a secreted protein that is highly abundant in the cornea. Mutations in only one of the two copies of the TGFBIp gene found in each cell are associated with corneal dystrophies, where protein accumulation in the cornea leads to interference with, and ultimately loss of, vision. The disease mechanism of TGFBI corneal dystrophy is not known and the current treatments only offer temporary relief due to the reoccurrence of deposits. Using in vitro molecular and cellular techniques, our laboratory has developed gene therapies which aim to specifically reduce expression of damaging mutant proteins, while leaving the normal protein unaffected.

Ultimately, the success of gene therapy approaches will be judged by prevention of the appearance of corneal deposits and/or progression of the disease after diagnosis in patients.  However, prior to clinical trials of gene silencing and gene editing therapies commencing, a deeper understanding of the mechanisms of deposit formation and additional measures of corneal disease are required.

The successful candidate will conduct cutting-edge research in state-of-the art facilities and gain wide experience in a variety of cell and molecular biology techniques. Samples from patients and mouse models of disease will be used. The student will join a group with both national and international collaborations and two key industrial partners that will allow pursuit of research towards the prevention of these debilitating genetic diseases.

The applicant should have experience of undertaking a research project, good communication and organisational skills, experience of effective team working and an ability and willingness to learn new skills and techniques, undertake scientific writing and to travel.

Please note: Applications for more than one PhD studentship are welcome, however if you apply for more than one PhD project within Biomedical Sciences, your first application on the system will be deemed your first-choice preference and further applications will be ordered based on the sequential time of submission. If you are successfully shortlisted, you will be interviewed only on your first-choice application and ranked accordingly. Those ranked highest will be offered a PhD studentship. In the situation where you are ranked highly and your first-choice project is already allocated to someone who was ranked higher than you, you may be offered your 2nd or 3rd choice project depending on the availability of this project.

Essential criteria

Applicants should hold, or expect to obtain, a First or Upper Second Class Honours Degree in a subject relevant to the proposed area of study.

We may also consider applications from those who hold equivalent qualifications, for example, a Lower Second Class Honours Degree plus a Master’s Degree with Distinction.

In exceptional circumstances, the University may consider a portfolio of evidence from applicants who have appropriate professional experience which is equivalent to the learning outcomes of an Honours degree in lieu of academic qualifications.

  • Sound understanding of subject area as evidenced by a comprehensive research proposal
  • Clearly defined research proposal detailing background, research questions, aims and methodology

Desirable Criteria

If the University receives a large number of applicants for the project, the following desirable criteria may be applied to shortlist applicants for interview.

  • Completion of Masters at a level equivalent to commendation or distinction at Ulster
  • Experience using research methods or other approaches relevant to the subject domain
  • Work experience relevant to the proposed project
  • Publications record appropriate to career stage
  • Experience of presentation of research findings
  • A comprehensive and articulate personal statement
  • Relevant professional qualification and/or a Degree in a Health or Health related area

Funding and eligibility

The University offers the following levels of support:

Vice Chancellors Research Studentship (VCRS)

The following scholarship options are available to applicants worldwide:

  • Full Award: (full-time tuition fees + £19,000 (tbc))
  • Part Award: (full-time tuition fees + £9,500)
  • Fees Only Award: (full-time tuition fees)

These scholarships will cover full-time PhD tuition fees for three years (subject to satisfactory academic performance) and will provide a £900 per annum research training support grant (RTSG) to help support the PhD researcher.

Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.

Please note: you will automatically be entered into the competition for the Full Award, unless you state otherwise in your application.

Department for the Economy (DFE)

The scholarship will cover tuition fees at the Home rate and a maintenance allowance of £19,000 (tbc) per annum for three years (subject to satisfactory academic performance).

This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.

  • Candidates with pre-settled or settled status under the EU Settlement Scheme, who also satisfy a three year residency requirement in the UK prior to the start of the course for which a Studentship is held MAY receive a Studentship covering fees and maintenance.
  • Republic of Ireland (ROI) nationals who satisfy three years’ residency in the UK prior to the start of the course MAY receive a Studentship covering fees and maintenance (ROI nationals don’t need to have pre-settled or settled status under the EU Settlement Scheme to qualify).
  • Other non-ROI EU applicants are ‘International’ are not eligible for this source of funding.
  • Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.

Due consideration should be given to financing your studies. Further information on cost of living

Recommended reading

Publications on this work from the group include-

Gene Editing for Corneal Stromal Regeneration. Moore, T. C. B., et al. 2020. Methods in Molecular Biology. Vol. 2145. p. 59-75

Mutation-independent Allele-Specific Editing by CRISPR-Cas9, a Novel Approach to Treat Autosomal Dominant Disease. Christie, K. et al. 2020. Molecular Therapy. 28, 1846-1857

Protein Analysis of the TGFBI R124H Mouse Model Gives Insight Into Phenotype Development of Granular Corneal Dystrophy. Lukassen, M. V. et al. 2020. Proteomics - Clinical Applications. 14, 1900072.

Topical siRNA delivery to the cornea and anterior eye by hybrid silicon-lipid nanoparticles.Baran-Rachwalska, P. et al. 2020. Journal of Controlled Release. 326, 192-202.

Biochemical mechanisms of aggregation in TGFBI-linked corneal dystrophies.

Nielsen, N. S. et al. 2020. Progress in Retinal and Eye Research. 77, 100843.

Capsid Engineering Overcomes Barriers Toward Adeno-Associated Virus Vector-Mediated Transduction of Endothelial Cells. Zhang, L. et al. 2019. Human Gene Therapy. 30, 1284-1296.

Effective In Vivo Topical Delivery of siRNA and Gene Silencing in Intact Corneal Epithelium Using a Modified Cell Penetrating Peptide. Schiroli, D., et al. 2019. Molecular Therapy - Nucleic Acids. 17, 891-906.

Late-Onset Lattice Corneal Dystrophy Associated TGFBI p.H626R Mutation in Members of a Canadian Family. Chao-Shern, C. et al. 2019. Canadian Journal of Ophthalmology. 54, e308-e311.

Evaluation of TGFBI corneal dystrophy and molecular diagnostic testing. Chao-Shern, C. et al. 2019. Eye 33, 874-881.

Personalised genome editing – The future for corneal dystrophies. Moore, C. B. T. et al, 2018. Progress in Retinal and Eye Research 65,147-165.

Post-LASIK Exacerbation of Granular Corneal Dystrophy Type 2 in Members of a Chinese Family. Chao-Shern, C. et al. 2018. Eye 32, 39-43.

Towards personalised allele-specific CRISPR gene editing to treat autosomal dominant disorders. Christie, K. et al. 2017. Scientific Reports. 7, 16174.

Repair of the TGFBI gene in human corneal keratocytes derived from a granular corneal dystrophy patient via CRISPR/Cas9-induced homology-directed repair. Yukako, T. et al. 2017, Scientific Reports. 7, 1-7.

Keratin 12 missense mutation induces the unfolded protein response and apoptosis in Meesmann epithelial corneal dystrophy. Allen, E. et al. 2016. Human Molecular Genetics. 25, 1176-1191.

CRISPR/Cas9 DNA cleavage at SNP-derived PAM enables both in vitro and in vivo KRT12 mutation-specific targeting. Courtney, D. G., et al. 2015. Gene Therapy. 23, 108-112.

Protein Composition of TGFBI-R124C- and TGFBI-R555W- Associated Aggregates Suggests Multiple Mechanisms Leading to Lattice and Granular Corneal Dystrophy. Courtney, D. G. et al. 2015 Investigative Ophthalmology & Visual Science. 56, 4653-4661.

Development of Allele-Specific Gene-Silencing siRNAs for TGFBI Arg124Cys in Lattice Corneal Dystrophy Type I. Courtney, D. G. et al. 2014, Investigative Ophthalmology & Visual Science. 55, 977-985.

siRNA Silencing of the Mutant Keratin 12 Allele in Corneal Limbal Epithelial Cells Grown from Patients with Meesmann’s Epithelial Corneal Dystrophy. Courtney, D. G. et al. 2014. Investigative Ophthalmology & Visual Science. 55,3352-3360.

Allele-specific siRNA silencing for the common Keratin 12 founder mutation in Meesmann epithelial corneal dystrophy. Allen, EHA. et al. 2013, Investigative Ophthalmology & Visual Science 54, 494-502.

The Doctoral College at Ulster University

Key dates

Submission deadline
Monday 27 February 2023
04:00PM

Interview Date
27 March to 6 April 2023

Preferred student start date
18 September 2023

Applying

Apply Online  

Contact supervisor

Dr Andrew Nesbit

Other supervisors