Determining how healthy, physiologically-relevant exposure to inflammatory factors affects chondrocyte secretory and post-transcriptional responses.

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，具有特殊的表型，在发育过程中开始，然后在我们的一生中保持。软骨细胞表型的成功维持对于健康衰老是重要的，而在尝试设计新鲜组织时，提高对表型诱导的理解是极其重要的。我们的团队对转录后基因调控如何影响软骨功能感兴趣，在利物浦，我们的研究特别关注信使RNA （mRNA）衰变或蛋白质翻译率变化的重要性。该项目提供了一个令人兴奋的机会，通过使用尖端的基因编辑方法，实验研究转录后调节机制如何促进软骨细胞功能。这项工作将集中在软骨细胞对炎症介质的反应上，这种反应通常在健康关节或遭受急性机械应力的关节中观察到。这是一个新的领域，因为炎症因子通常用于软骨细胞研究，在非自然的高水平产生组织破坏和模型疾病。该项目旨在确定这些因素在与健康组织环境相关的浓度下调节的过程。该项目将使用Crispr/Cas9方法来破坏重要的炎症信号过程，以确定软骨细胞对炎症因子暴露的生理相关水平的原发性和继发性反应。这项工作将描述这些反应是如何在分子水平上介导的，检查转录、转录后和分泌反应。

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 have a specialised phenotype that is initiated during development and then maintained throughout our lives. Successful maintenance of the chondrocyte phenotype is important for healthy ageing, whilst improved understanding of phenotype induction is extremely important when trying to engineer fresh tissue. Our groups are interested in how post-transcriptional gene regulation influences cartilage function, in Liverpool our research is particularly focused on the importance of variation in messenger RNA (mRNA) decay or protein translation rates. This project offers an exciting opportunity to experimentally examine how post-transcriptional regulatory mechanisms contribute to cartilage cell function through the use of cutting-edge gene editing approaches. The work will focus on the chondrocyte response to inflammatory mediators at levels normally observed in healthy joints or those that have suffered acute mechanical stress. This is a novel area because inflammatory factors are usually employed in chondrocyte studies at unnaturally high levels to generate tissue breakdown and model disease. This project aims instead to determine the processes modulated by such factors in at concentrations relevant to the healthy tissue environment.The project will use Crispr/Cas9 methodology to disrupt important inflammatory signalling process to determine the primary and secondary responses of chondrocytes to physiologically-relevant levels of exposure to inflammatory factors. The work will characterise how these responses are mediated at the molecular level, examining transcriptional, post transcriptional and secretory responses.