Understanding how secretory responses shape the downstream response of chondrocytes to inflammatory cytokine stimulation

Healthy cartilage in our joints is essential for us to maintain an active life into old age. The cells that maintain cartilage are called chondrocytes and maintenance of their phenotype is important for healthy ageing. Inflammation is often a characteristic of an injured or diseased joint and excessive inflammatory stimulation has a negative effect on the integrity of the tissues within it. However, evidence suggests that some degree of inflammatory signalling is important for fundamental joint health although the mechanisms behind this have not been systematically investigated. This project will aim to map the consequences of inflammatory stimulation on chondrocyte function by examining how transient, physiologically relevant levels of inflammatory regulators called cytokines affect molecular signalling and downstream secretion of further inflammatory factors. Uniquely, it will utilise CRISPR/Cas9 gene editing technology to develop knockout cell lines that will allow us to tease apart the mechanisms affected in both the primary inflammatory stimulus and any secondary chondrocyte inflammatory responses. In addition, co-culture models using cells from different joint tissues will be employed to determine whether secondary, secretory responses to cytokine signalling can contribute to healthy cross talk between tissues within the joint. The student will be primarily placed at the University of Liverpool, in the group of Dr Simon Tew, who been studying molecular regulation of chondrocytes for many years. In addition, the project involves placement periods with Professor David Young at Newcastle University, whose laboratory has developed up a variety of functional gene editing and regulation models using Crispr/Cas9 technology