The pro-survival effect of Urocortin1 on articular chondrocytes through modulation of calcium influx

点击翻译按钮获取中文摘要

Control of cell survival in response to injurious pro-apoptotic stimuli is essential for maintenance of cell and tissue health during ageing and an excess of pro-apoptotic stimuli can lead to cell death and to age-related disease. In articular cartilage, the resident cell population (chondrocytes) are exposed to a wide range of extrinsic pro-apoptotic stimuli which have been shown to result in a decrease in chondrocyte number and ultimately in osteoarthritis. It is thus essential to understand the key regulatory pathways involved in chondrocyte survival (as a model cell type) in response to increased pro-apoptotic stimuli to enable healthy ageing.Importantly, we have identified urocortin-1 (Ucn1) as a potent pro-survival factor in chondrocytes and have preliminary evidence that Ucn1 exerts its protective effect by modulating a non-selective cation channel. Thus, we hypothesise that Ucn1-Ca2+signalling is an essential axis for control of cell survival following exposure to extrinsic pro-apoptotic stimuli, such as increased NO levels, or excessive mechanical stress. Therefore, using chondrocytes as a model system in which extrinsic pro-apoptotic stimuli are responsible for causing an age-related decline in cell number, we now seek to investigate the molecular basis of this antagonist-induced cell death and Ucn1 mediated protection from NO and excessive mechanical load.To investigate these hypotheses, the student will first work to identify the non-selective cation channel at work in this system, through use of an si-RNA screening plate. They will utilise primary human cell stimulation (e.g. NO), along with pharmacological inhibition studies and a range of state-of-the-art analytical techniques. Additionally, complex cartilage loading parameters will be modelled and applied to assess the effect of injurious load upon chondrocyte health in both porcine and human osteoarthritic cartilage.