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

我们关节中的健康软骨对我们保持活跃的生活到老年至关重要。维持软骨的细胞被称为软骨细胞，其表型的维持对于健康衰老是重要的。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，一定程度的炎症信号对基本关节健康很重要，尽管其背后的机制尚未得到系统的研究。该项目旨在通过检查称为细胞因子的炎症调节因子的瞬时生理相关水平如何影响分子信号传导和下游进一步炎症因子的分泌来绘制炎症刺激对软骨细胞功能的后果。独特的是，它将利用CRISPR/Cas9基因编辑技术开发敲除细胞系，使我们能够区分原发性炎症刺激和任何继发性软骨细胞炎症反应中受影响的机制。此外，将采用使用来自不同关节组织的细胞的共培养模型来确定对细胞因子信号传导的次级分泌反应是否有助于关节内组织之间的健康串扰。这名学生将主要被安排在利物浦大学的Simon Tew博士小组，他多年来一直在研究软骨细胞的分子调控。此外，该项目还包括与纽卡斯尔大学的大卫杨教授的实习期，他的实验室使用Crispr/Cas9技术开发了各种功能性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