Research Scholarships 2019: Project 4

Serpin variants as potential therapeutics in bone and skeletal disease

PI: Assoc. Professor Margaret Worrall

The serpins (serine protease inhibitors) are a superfamily of proteins, which act as natural inhibitors of plasma proteolytic processes including coagulation and fibrinolysis, but can also have other properties ranging from tumour suppression to hormone transport.  Serpins are suicide inhibitors that form an irreversible complex with a target serine or cysteine protease. SerpinB3 (also SCCA-1, squamous cell carcinoma antigen 1) inhibits cysteine cathepsins L, S, K, V and related parasite proteases. The research group in UCD has modified the reactive centre loop of this protein to generate a more potent inhibitor of cathepsin K, a protease implicated in cartilage degradation and bone disease. In this project you will further characterise the efficacy of recombinant serpinB3 variants to inhibit catK activity in in vitro models of disease. The use of serpins as therapeutic agents has precedence, the most documented being administration of recombinant alpha-1-antitrypsin (AAT) for emphysema and liver disease caused by AAT deficiency.  However, SerpinB3 and the closely related serpinB4, have also been found to generate an autoantigen pso p27 that is found in psoriasis and may be present in other inflammatory diseases (Iversen et al, 2017). In this case these serpins may present a useful target for therapy, and a further objective in this project is to investigate the processing mechanism for pso p27 generation using a site directed mutagenesis approach.  A suitable candidate will have a background in Biochemistry or related degree subject.
 
Enquiries and applications (to include cover letter and CV) to Assoc. Prof. Margaret Worrall. Email: mworrall@ucd.ie
 
Closing date: Friday 31st May 2019.