Idiopathic Pulmonary Fibrosis (IPF) is an ageing-associated, debilitating lung disease affecting mainly men over 60 years of age. Prognosis is poor with treatment options limited to antifibrotics and other interventions seeking to arrest lung function decline. No cures exist due to the extensive need for tissue regeneration. Preventative approaches are limited by the fact that symptoms occur only at a point that tissue damage is generally irreversible.
A number of Genome Wide Association Studies (GWAS) have reproducibly identified a single nucleotide polymorphism (SNP) in the promoter of mucin 5 b (MUC5B) with an approximately 40% association with the disease. The polymorphism is thought to alter CpG island structure, altering methylation status and transcription factor recruitment, resulting in non-canonical overexpression of MUC5B across lung epithelia. Crucially, this also occurs in the alveoli where mucin expression is normally absent. It is postulated that alveolar cells enter into endoplasmic reticulum (ER) stress as they degrade mucin 5b protein to prevent its’ release into the lung lumen and consequently alveolar dysfunction. The elevated (ER) stress then makes these cells more susceptible to cell damage and death, underpinning the chronic tissue degeneration that over the years leads to late age symptom onset.
We have recently identified a novel, promoter-associated non-coding RNA transcript (paRNA) in the promoter of MUC5B, expressed specifically in lung epithelial cells. The transcript appears to be subject to splicing and, crucially, the SNP in the MUC5B promoter associated to IPF appears to reside in a splice acceptor site of the paRNA. This project seeks to explore the functional role of this ncRNA in MUC5B expression regulation, by dissecting the molecular impact of the SNP in paRNA splicing, binding partner recruitment, and function.
You will work with Associate Professor Sterghios A. Moschos and Dr. Antony Antoniou, in collaboration with Prof. Manfred Frick (University of Ulm, Germany). You will train and use our world class third generation sequencing and proteomics facilities recently upgraded through an 8 million UKRI grant, and acquire advanced skills in air liquid interface culture (primary cells) in these fundamental molecular studies. The project will develop new cell biology tools for the study of IPF, evaluate the relative cytoprotective effects of paRNA intervention vs MUC5B silencing and SNP editing, and seek to define a strategy for pre-emptive genomic therapy in SNP carriers in the future.
Eligibility and How to Apply:
Please note eligibility requirement:
• Academic excellence of the proposed student i.e. 2:1 (or equivalent GPA from non-UK universities [preference for 1st class honours]); or a Masters (preference for Merit or above); or APEL evidence of substantial practitioner achievement.
• Appropriate IELTS score, if required.
For further details of how to apply, entry requirements and the application form, see https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/
Please note: Applications should include a covering letter that includes a short summary (500 words max.) of a relevant piece of research that you have previously completed. Applications that do not include the advert reference (e.g. SF20/…) will not be considered.
Deadline for applications: 1st July for October start, or 1st December for March start
Start Date: October or March
Northumbria University takes pride in, and values, the quality and diversity of our staff. We welcome applications from all members of the community. The University holds an Athena SWAN Bronze award in recognition of our commitment to improving employment practices for the advancement of gender equality.
Please direct enquiries to Dr Sterghios Moschos ([email protected]
Graves, H. & Moschos, S. A. Measuring the action of oligonucleotide therapeutics in the lung at the cell type level. Methods Mol. Biol. 2019, 2036:187-203
Moschos, S.A, Usher, L., & Lindsay M.A. Clinical potential of oligonucleotide-based therapeutics in the respiratory system. Pharmacology & Therapeutics, 2017, 169:83-103
Cucurull-Sanchez, L., Spink, K. & Moschos, S.A. Relevance of systems pharmacology in drug discovery. Drug. Discov. Today 2012, 17(13-14):665-70.
Moschos, S.A., Frick, M., Taylor, B., et al. Uptake, efficacy & systemic distribution of naked, inhaled short interfering RNA (siRNA) & locked nucleic acid (LNA) antisense. Mol. Ther. 2011, 19(12):2163-8.
Tsitsiou, E., Williams, A.E., Moschos, S.A., Jiang, X., Adams, O.D., Patel, K., Macedo, P., Woodcock, A., Fidock, M., Chung, K.F., & Lindsay, M.A. Transcriptome analysis show activation of circulating CD8+ T-cells in patients with severe asthma, J. Allergy Clin. Immunol. 2011, 129(1):95-103.
Perry, M.M., Moschos, S.A., Williams, A.E., Shepherd, N.J., Larner-Svensson, H.M., & Lindsay, M.A. Rapid changes in microRNA-146a expression negatively regulate the IL-1beta-induced inflammatory response in human lung alveolar epithelial cells. J. Immunol. 2008, 180(8):5689-98.