Idiopathic Pulmonary Fibrosis (IPF) is an ageing-associated, debilitating lung disease that manifests mainly in 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 and preventative approaches are limited by the onset of symptoms typically only after the extent of tissue damage is generally irreversible.
A number of Genome Wide Association Studies (GWAS) carried out across the world 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 in the promoter of MUC5B, 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, and deleterious to oxygen exchange. It is postulated that alveolar cells enter into endoplasmic reticulum stress due to the need to degrade mucin 5b protein to prevent alveolar dysfunction, making them more susceptible to cell damage and death, underpinning the chronic tissue degeneration leading 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 locate proximally to the splice acceptor site. This project seeks to explore the functional role of this ncRNA in MUC5B expression regulation, by dissecting the molecular impact of the SNP in MUC5B paRNA splicing, binding partner recruitment, and function.
The successful candidate will train or implement their experience in RNA SEQ, cell culture, genome editing, or oligonucleotide manipulation of RNA molecules to document the physiological impacts of the SNP on the MUC5B promoter microcircuitry, and cellular function.
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.
• Applicants cannot apply for this funding if currently engaged in Doctoral study at Northumbria or elsewhere.
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 and the reasons you consider yourself suited to the project. 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.