How do mammalian cells handle mRNA therapeutics: Optimising the molecular basis of manufacture

哺乳动物细胞如何处理 mRNA 疗法：优化制造的分子基础

• 批准号: 2903763
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2903763
• 关键词: How; do; mammalian; cells; handle

The use of mRNA to generate vaccines against COVID-19 has cemented the potential for nucleic acids to develop approaches to prevent viral infection and to have wider applications in the treatment of life-threatening cancers (Nature [2021] 589: 189-191; The Lancet [2022] 23: e450-e458). To maximise the potential of mRNA (and other nucleic acid-based therapeutics) we need to understand more about their delivery into cells, intracellular handling/stability and the processes that link cellular localisation to effective expression. We also need to determine if findings are generic to cell types or if processes can be optimised for specific cell types and status. This provides the overall aim for your project. The specific objectives of your project will require you to (i) generate a panel of mRNA products (ii) examine the uptake, processing and expression within a panel of cultured mammalian cells, (iii) screen host cell phenotype in response to the extent of product expression, (iv) use machine learning methods to understand changes in metabolic pathways upon uptake of mRNA products by mammalian cells and (v) test hypotheses derived by engineering specific cellular functionalities. In achieving these objectives you will master a wide range of analytical, cellular and molecular techniques, including fluorescence microscopy, high resolution mass spectrometry assays, omics data interrogation, chemometrics methods, data interpretation and cellular and process engineering. Working with the Centre for Process Innovation (CPI) RNA Centre of Excellence (https://www.uk-cpi.com/about/national-centres/rna-centre-of-excellence) we will be part of a wider vision to innovate design and manufacture of RNA vaccines and therapeutics.

使用mRNA产生针对COVID-19的疫苗巩固了核酸开发预防病毒感染的方法的潜力，并在治疗危及生命的癌症中具有更广泛的应用（Nature [2021] 589：189-191; The Lancet [2022] 23：e450-e458）。为了最大限度地发挥mRNA（和其他基于核酸的疗法）的潜力，我们需要更多地了解它们向细胞中的递送、细胞内处理/稳定性以及将细胞定位与有效表达联系起来的过程。我们还需要确定这些发现是否对细胞类型具有通用性，或者是否可以针对特定的细胞类型和状态进行优化。这为您的项目提供了总体目标。您的项目的具体目标将要求您（i）生成一组mRNA产物（ii）检查一组培养的哺乳动物细胞内的摄取，加工和表达，（iii）筛选响应产物表达程度的宿主细胞表型，（iv）使用机器学习方法来了解哺乳动物细胞摄取mRNA产物后代谢途径的变化，以及（v）通过工程化特定细胞功能来测试假设。在实现这些目标，你将掌握广泛的分析，细胞和分子技术，包括荧光显微镜，高分辨率质谱分析，组学数据查询，化学计量学方法，数据解释和细胞和过程工程。与过程创新中心（CPI）RNA卓越中心（https：//www.uk-cpi.com/about/national-centres/rna-centre-of-excellence）合作，我们将成为RNA疫苗和治疗剂创新设计和制造的更广泛愿景的一部分。