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Engineering cellular stress for enhanced extracellular bioproduction

工程细胞应激以增强细胞外生物生产

基本信息

批准号：
BB/T005742/1
负责人：
Neil Dixon
金额：
$ 65.72万
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FT005742%2F1
关键词：
Engineering cellular stress enhanced extracellular

项目摘要

The production of recombinant protein is powerful technique widely employed in biology research labs around the world and for the industrial-scale production of therapeutic proteins and industrial enzymes. Within the pharmaceutical sector, protein-based biopharmaceuticals constitute 8 out of the 10-bestselling products, and the global protein-based biopharmaceutical market had sales worth $120b in 2017. A major component of the manufacturing cost of these products is associated with extraction of the product from the host production cells, and isolation and purification procedures. This has a major impact upon the affordability and equitable global access to biologic-medicines once off patent, as the high manufacturing cost limits possible price reductions when compared to small-molecule generic medicines. As such, adoption of new methods to facilitate the isolation of high purity and quality product, would offer great benefit in reducing the cost and challenges, and hence benefit society. Proteins destined for secretion out of host cells are directed toward the secretion pathways by the presence of specific signal peptides. However, in a recent study we demonstrated that under conditions of stress bacterial cells, which are commonly used for recombinant protein production, undergo an excretion phenomenon whereby proteins are translocated into the extracellular environment, even without a signal peptide. Confirming the presence of alternative translocation/excretion pathways and understanding their function and regulation are thus important for fundamental microbiology and biotechnology. In this study we will seek to understand and harness this excretion phenomenon for the biotechnological production of protein-based biopharmaceuticals. The potential to more effectively produce these medicines, used in the treatment of diabetes or certain cancers, could lower the cost of the therapy and so reduce the burden upon healthcare providers, e.g. the NHS. Within this study will seek to understand the ability of E. coli cells to excrete and produce biopharmaceuticals with enhanced productivity. This research project will generate technology and knowledge that will help maintain the UK's competitive edge, and will produce highly trained and skilled research personnel.

重组蛋白的生产是一种强大的技术，广泛应用于世界各地的生物学研究实验室以及治疗性蛋白和工业酶的工业规模生产。在制药领域，蛋白质生物制药占据了 10 个最畅销产品中的 8 个，2017 年全球蛋白质生物制药市场的销售额为 1200 亿美元。这些产品制造成本的主要组成部分与从宿主生产细胞中提取产品以及分离和纯化程序有关。一旦专利到期，这将对全球生物药品的可负担性和公平获取产生重大影响，因为与小分子仿制药相比，高制造成本限制了可能的降价。因此，采用新方法来促进高纯度和高质量产品的分离，将在降低成本和挑战方面带来巨大好处，从而造福社会。由于特定信号肽的存在，注定要分泌出宿主细胞的蛋白质被引导至分泌途径。然而，在最近的一项研究中，我们证明，在应激条件下，通常用于重组蛋白生产的细菌细胞会经历排泄现象，即使没有信号肽，蛋白质也会被转移到细胞外环境中。因此，确认替代易位/排泄途径的存在并了解其功能和调节对于基础微生物学和生物技术非常重要。在这项研究中，我们将寻求理解和利用这种排泄现象来进行基于蛋白质的生物制药的生物技术生产。更有效地生产这些用于治疗糖尿病或某些癌症的药物的潜力可以降低治疗成本，从而减轻医疗保健提供者的负担，例如医疗保健提供者的负担。国民医疗服务体系。在这项研究中，我们将寻求了解大肠杆菌细胞排泄和生产生物药物的能力，从而提高生产力。该研究项目将产生有助于保持英国竞争优势的技术和知识，并将培养训练有素、技术精湛的研究人员。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

arfA antisense RNA regulates MscL excretory activity.

ARFA反义RNA调节MSCL排泄活性。

DOI：
10.26508/lsa.202301954
发表时间：
2023-06
期刊：
Life science alliance
影响因子：
4.4
作者：
通讯作者：

arfA antisense RNA regulates MscL excretory activity

DOI：
10.1101/2022.11.21.517365
发表时间：
2022-11
期刊：
Life Science Alliance
影响因子：
4.4
作者：
R. Morra;Fenryco Pratama;Thomas M. Butterfield;Geizecler Tomazetto;Kate Young;R. López;N. Dixon
通讯作者：
R. Morra;Fenryco Pratama;Thomas M. Butterfield;Geizecler Tomazetto;Kate Young;R. López;N. Dixon