Project Reference: TRG27-PHA-ES1

Project title: Neuroimmune cross talk in joint homeostasis

Project outline

Throughout a mammal’s life different forms of joint stress occur, for example, biomechanical injury and ageing. Sensory neurons innervating the joint are bathed in synovial fluid, the characteristics of which change during stress, from cell types and mediators present to the pH. Changes in joint pH can stimulate nerves to cause pain but can also stimulate non-neuronal cells within the joint, such as synoviocytes and chondrocytes, as well as immune cells, which in turn release mediators that drive disease pathogenesis. This project will focus on understanding how proton-sensing G protein-coupled receptors (PS-GPCRs) expressed by different cell types contribute to joint homeostasis. Specifically, we will focus on GPR65, which is expressed by non-neuronal cells like synoviocytes, and GPR68, which is primarily expressed on sensory neurons. To support this project, pharmacological tools and knockout mice will enable interrogation of how stimulation of GPR65 and GPR68 in different cell types present within the joint alters their biology: what signalling cascades are activated, which mediators are released and how does cell-cell cross talk modulate function? For example, how does conditioned medium obtained from GPR65 stimulated chondrocytes, macrophages, and synoviocytes alter sensory neuron activity and how does loss of GPR68 alter neuronal acid-sensitivity? Results from these experiments will enhance our understanding of how activation of different pH sensors contributes to changes in cell biology and, in turn, joint homeostasis. In vitro studies will be complemented by in vivo studies in young vs. old mice to determine how naturally occurring, age-induced osteoarthritis is altered in mice that lack GPR65 and GPR68. Overall, this project will generate results informing on the contribution of GPR65 and GPR68 to the biology of different joint cell types and the role each receptor plays in relation to age-associated joint stress.

Principal Supervisor

Professor Ewan Smith

Email address: es336@cam.ac.uk

Department / Partner Institute: Pharmacology

Website: https://www.phar.cam.ac.uk/research/Smith

BBSRC strategic theme

Understanding the rules of life