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The University of Sheffield
Faculty of Medicine, Dentistry & Health
Department of Cardiovascular Science
Determining the biological and prognostic significance in pulmonary arterial hypertension of
identified SNPs in osteoprotegerin.
Supervisor: Dr Allan Lawrie & Dr Martina Daly
Project:
Pulmonary Arterial Hypertension (PAH) is a rare disease defined by cardiac
catheterisation as a mean pulmonary artery pressure of at least 25 mmHg. Patients
with PAH have significant morbidity and, if untreated, a median survival of 2.8 years.
Pathologically, PAH is characterised by progressive narrowing of small resistance
pulmonary arteries and arterioles due to a process of vascular cell proliferation and
inflammatory cell infiltration. We have previously identified that the protein
osteoprotegerin (OPG) in upregulated in pulmonary vascular lesions and serum
from patients with PAH. We have recently demonstrated that OPG is required for
the development of PAH in experimental models, and furthermore, that treatment
with an anti-OPG antibody reverses disease in these models. Preliminary data has
identified 3 rare haplotypes of the gene encoding OPG in patient samples obtained
from the Sheffield Pulmonary Hypertension Biobank and shown that the rare allele
of a non-synonymous single nucleotide polymorphism (SNP) in Exon 1 of the gene
is more common in Idiopathic PAH, associated with higher serum levels of OPG and
predicts a poor prognosis. The aim of this project is to study the genotype to
phenotype relationship of these SNPs using a combination of site-directed
mutagenesis and expression studies.
Entry Requirements:
Candidates must have a first or upper second class honors degree or significant
research experience.
Enquiries:
Interested
candidates
should
([email protected]).
How to apply:
in
the
first
instance
contact
Allan
Lawrie
Please complete a University Postgraduate Research Application form and attach at
least two references to your application. To complete the application form please
visit: www.shef.ac.uk/postgraduate/research/apply.
Please clearly state the prospective main supervisor in the respective box and select
‘Medicine’ as the department.
Website: http://www.shef.ac.uk/cardiovascularscience
Closing date: To be agreed