Postdoctoral Research Associate - Grade 7

A full-time postdoctoral position is available in the lab of Dr David Wilkinson in the Department of Musculoskeletal and Ageing Science. This exciting, multidisciplinary project, funded by the BBSRC, aims to understand the role of serine proteinase inhibitors (serpins) in cartilage development. The successful candidate will join a supportive and inclusive lab environment, and benefit from diverse project team skill and expertise.

The successful candidate should have a PhD in cartilage, stem cell or protease biology (or a related discipline). Expertise in mammalian cell culture, biochemical/protein methods (e.g. immunoprecipitation (IP), mass spectrometry) and molecular biology are essential. Experience in stem cell differentiation, fluorescence microscopy and CRISPR/Cas9 gene editing are desirable. Previous experience of in vivo models would also be advantageous.

Summary

Serine proteinase inhibitors (serpins) are a superfamily of structurally similar proteins that regulate many processes, from blood coagulation to extracellular matrix (ECM) homeostasis. Most serpins are inhibitory, and use a covalent mode of inhibition to inhibit their target serine proteinases (1). We and others have suggested serpins are important in the context of cartilage, and are highly regulated in diseases such as osteoarthritis (2).

Recently, we have demonstrated that one serpin, SERPINA3 (aka alpha-1 antichymotrypsin), is highly induced during cartilage formation (chondrogenesis) in vitro, and that silencing of this gene blocks the induction of the key ECM genes required (3). Although considered an extracellular inhibitor, SERPINA3 also has a DNA-binding domain, and we can detect SERPINA3 in chondrocytes intracellularly.

In this project, you will take a comprehensive approach to study SERPINA3 in chondrogenesis. You will identify binding partners and establish how it regulates intracellular signalling pathways. You will make CRISPR mutant lines, to establish how the protein itself facilitates the differentiation process (with Co-I Prof David Young, Newcastle University). You will also establish the importance of SERPINA3 in cartilage development using a Xenopus model, in the lab of the Co-I, Prof Grant Wheeler (University of East Anglia). An improved understanding of key factors regulating cartilage formation, could have important implications for regenerative medicine strategies for joint diseases such as osteoarthritis.

Suggested reading

1. Wilkinson DJ. Serpins in cartilage and osteoarthritis: what do we know? Biochem Soc Trans. 2021. Apr 30;49(2):1013-1026.
2. Wilkinson DJ, Falconer AMD, Wright HL, Lin H, Yamamoto K, Cheung K, Charlton SH, Arques MdC, Janciauskiene S, Refaie R, Rankin KS, Young DA, Rowan AD. Matrix metalloproteinase-13 is fully activated by neutrophil elastase, and inactivates its serpin inhibitor, alpha-1 antitrypsin: Implications for osteoarthritis. FEBS J. 2022 Jan;289(1):121-139.
3. Barter MJ, Turner DA, Rice SJ, Hines M, Lin H, Falconer AMD, McDonnell E, Soul J, Del Carmen Arques M, Europe-Finner GN, Rowan AD, Young DA, Wilkinson DJ. SERPINA3 is a marker of cartilage differentiation and is essential for the expression of extracellular matrix genes during early chondrogenesis. Matrix Biol. 2024 Aug 1:S0945-053X(24)00095-7.

This post is fixed term until 31^st October 2028.

If you are still awaiting your PhD to be awarded you will be appointed at Grade 6, spine point 30.  Upon written confirmation that you have been awarded your PhD, your salary will be increased to Grade 7, spine point 31.

Commitment to Diversity

The university is committed to enhancing workforce diversity. We actively seek to attract, develop, and retain colleagues with diverse backgrounds and perspectives. We welcome applications from all genders/gender identities, Black, Asian, or Minority Ethnic backgrounds, individuals living with a disability, and members of the LGBTQIA+ community.

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