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

关节中健康的软骨对我们进入老年后保持活跃的生活至关重要。维持软骨的细胞被称为软骨细胞，维持它们的表型对健康衰老很重要。炎症通常是受伤或患病关节的特征，过度的炎症刺激对关节内组织的完整性有负面影响。然而，有证据表明，某种程度的炎症信号对基本的关节健康很重要，尽管其背后的机制尚未得到系统的研究。该项目旨在通过研究称为细胞因子的短暂的、生理相关的炎症调节因子水平如何影响分子信号传导和进一步炎症因子的下游分泌，来绘制炎症刺激对软骨细胞功能的影响。独特的是，它将利用CRISPR/Cas9基因编辑技术来开发敲除细胞系，这将使我们能够梳理出受原发性炎症刺激和任何继发性软骨细胞炎症反应影响的机制。此外，使用不同关节组织细胞的共培养模型将用于确定细胞因子信号的继发性分泌反应是否有助于关节内组织之间的健康串音。该学生将主要被安排在利物浦大学的Simon Tew博士的小组中，Simon Tew博士多年来一直在研究软骨细胞的分子调节。此外，该项目还包括纽卡斯尔大学David Young教授的实习期，他的实验室利用Crispr/Cas9技术开发了多种功能基因编辑和调控模型

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