Plasminogen-activator inhibitor (PAI-1) in the musculoskeletal system: a key serine proteinase inhibitor regulating joint homeostasis

Description

This PhD studentship will use in vitro, ex vivo and in vivo models to investigate the role of an important serine proteinase inhibitor (serpin) in the musculoskeletal system, leading to a better understanding of disease and opening new pathways to therapeutic intervention.

Osteoarthritis is one of the major causes of disability globally. Central to the disease is the breakdown of the articular cartilage on the surface of the joint. Cartilage protects the joint from compression and once lost, causes significant pain. The matrix metalloproteinases (MMPs) are a family of enzymes which drive the loss of the cartilage collagen, but despite this, MMPs are difficult to target with drugs, and attempts to do so have so far been unsuccessful (Young et al., 2019). The serine proteinases are a different family of proteinases which have emerging roles in the destruction of cartilage in OA, and more tractable drug targets as demonstrated for other disorders (Wilkinson et al., 2019).

Serine proteinase activity is controlled by their endogenous inhibitors – the largest family of which are the serpins, which have emerging roles in cartilage (reviewed in Wilkinson et al., 2021). Here we seek to investigate the role of a particularly interesting serpin – plasminogen activator inhibitor-1 (PAI-1) – in cartilage and bone development, and its role in the musculoskeletal system. We will use a combination of protein biology, cell-based models and PAI-1-deficient mice. We will study bone and cartilage changes using histology, microscopy and biochemical techniques when PAI-1 is absent or inhibited by pharmacological intervention targeting PAI-1 and seek to understand how it is regulated in both health and disease. Furthermore, there is good scope to develop the project and shape the research, based on interesting observations or the student’s own interests.

This PhD would be suitable for a motivated student interested in mechanism-based research in the field of musculoskeletal diseases and ageing. Candidates should have a good degree in biology, biochemistry or related Biological Sciences discipline. Working within the department of Musculoskeletal and Ageing Sciences in the Institute Life Course and Medical Sciences (ILCaMS), the successful candidate will be supervised by an interdisciplinary team at the University of Liverpool, led by Dr David Wilkinson. This opportunity will allow the successful candidate to explore the role an enigmatic serine proteinase inhibitor in the skeletal system.

The Institute of Life Course and Medical Science is fully committed to promoting gender equality in all activities. It aims to foster a supportive working environment and holds a silver Athena SWAN award in recognition of its on-going commitment to this.