Combined /omics approaches to understand and control library enriched microbial cell factories
组合/组学方法来理解和控制库富集的微生物细胞工厂
基本信息
- 批准号:BB/F004842/1
- 负责人:
- 金额:$ 37.96万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2008
- 资助国家:英国
- 起止时间:2008 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
The dynamic biological behaviour understanding needed for bioprocess development cannot be predicted solely by individual level /omic studies, since this approach only tells a proportion of the story. Therefore, we will implement an analytical technique, based on several different plasmid based genomic libraries (from two bacteria, Escherichia coli and Campylobacter jejuni) expressed in E. coli, coupled with measurements at the microarray (messenger RNA level) and proteome (protein complement of the cell) scale, to understand and improve the secreted glycosylated protein production bioprocess. Production of these types of proteins is very important to the pharmaceuticals industry, since nearly three quarters of proteins with human therapeutic importance are glycosylated (either released or in clinical and preclinical development). From the simplest to the most complex organisms, the process of transferring information from the genome to make proteins is universal and central to life. Understanding and quantifying this process is essential for scientific advancement. With such information it will become possible to manipulate organisms to achieve a desired biotechnological goal, such as production of proteins for medicinal purposes, and the replacement of synthetic chemicals. A genome sequence is the code for programming the way an organism functions. Sequencing the genome provides a database of information for identifying genes and assigning the potential function of these genes, and allows for comparison of similar genes across species. When genes switch on to start a biological function, a message is generated, that eventually makes a protein. Experimental technologies that exploit this message information across thousand of genes have been developed, such as SCALEs (multi-Scale Analysis of Library Enrichment). This field of information is known as transcriptomics. Transcriptomics, however, cannot be used solely to predict the dynamic biological behaviour needed for future biotechnology development, since this approach only tells a proportion of the story. The information missing from SCALEs is how these gene messages are used. What is needed is an integrated study of the message from the genome with the production of proteins. In order to achieve this, we also will implement an analytical technique, similar to SCALEs that will concentrate on the proteins rather than the genome. It is important to examine the protein complement of the organism (known as the proteome), because the observed physical health and behaviour of an organism is determined by the interaction of its genome with the environment, and this interaction is directly due to the proteins, rather than the genome, and its subsequent message (the transcriptome). Using our technique (called MLPPTM) which studies proteins, and experimental techniques such as SCALEs, which study the message from the genome, we will be able to provide an integrated study which generates a deeper knowledge of which proteins help give a cell certain properties. In this case, we seek to understand which proteins will give a cell an enhanced ability to generate glycosylated proteins (those with a linked oligosaccharide). This is important because the majority of proteins applied towards human heath applications are glycoproteins. Bacteria have not generally been thought of as being able to produce these proteins, and so more complicated organisms (eg from mammals), have been used instead. Bacteria are simpler to understand, grow faster and cheaper, and so would be very attractive if they could be designed to produce glycosylated proteins properly. The integrated transcriptomic and proteomic techniques examining E.coli containing overexpression libraries to be implemented here will allow us, when successful, to improve on glycosylated protein production in a bacterium, and set the scene for future efficient bioprocesses for making therapeutic proteins.
生物过程开发所需的动态生物行为理解不能仅仅通过个体水平/组学研究来预测,因为这种方法只讲述了故事的一部分。因此,我们将实施一种分析技术,基于在大肠杆菌中表达的几种不同的基于质粒的基因组文库(来自两种细菌,大肠杆菌和空肠弯曲杆菌)。大肠杆菌,加上在微阵列(信使RNA水平)和蛋白质组(细胞的蛋白质补体)规模的测量,以了解和改善分泌的糖基化蛋白质生产的生物过程。这些类型的蛋白质的生产对制药行业非常重要,因为具有人类治疗重要性的蛋白质中有近四分之三是糖基化的(释放或在临床和临床前开发中)。从最简单的生物到最复杂的生物,从基因组转移信息以制造蛋白质的过程是普遍的,也是生命的核心。理解和量化这一过程对科学进步至关重要。有了这些信息,就有可能操纵生物体,以实现预期的生物技术目标,例如生产用于医疗目的的蛋白质,以及取代合成化学品。基因组序列是生物体运作方式的编码。基因组测序为识别基因和分配这些基因的潜在功能提供了信息数据库,并允许跨物种比较相似基因。当基因启动生物功能时,就会产生一种信息,最终形成蛋白质。已经开发了在数千个基因中利用这种消息信息的实验技术,例如SCALEs(文库富集的多尺度分析)。这个信息领域被称为转录组学。然而,转录组学不能仅仅用于预测未来生物技术发展所需的动态生物行为,因为这种方法只讲述了故事的一部分。SCALEs缺少的信息是这些基因信息是如何被使用的。我们需要的是对基因组信息与蛋白质生产进行综合研究。为了实现这一目标,我们还将实施一种分析技术,类似于SCALE,它将集中在蛋白质而不是基因组上。检查生物体的蛋白质补充(称为蛋白质组)是很重要的,因为观察到的生物体的身体健康和行为是由其基因组与环境的相互作用决定的,这种相互作用直接归因于蛋白质,而不是基因组及其随后的信息(转录组)。使用我们研究蛋白质的技术(称为MLPPTM)和研究基因组信息的实验技术(如SCALE),我们将能够提供一种综合研究,从而更深入地了解哪些蛋白质有助于赋予细胞某些特性。在这种情况下,我们试图了解哪些蛋白质将使细胞产生糖基化蛋白质(具有连接寡糖的蛋白质)的能力增强。这很重要,因为大多数用于人类健康应用的蛋白质是糖蛋白。一般认为细菌不能产生这些蛋白质,因此使用了更复杂的生物(如哺乳动物)。细菌更容易理解,生长更快,更便宜,因此如果它们能够被设计成适当地生产糖基化蛋白质,那将是非常有吸引力的。这里实施的检测含有过表达库的大肠杆菌的综合转录组学和蛋白质组学技术,如果成功,将使我们能够改善细菌中糖基化蛋白的生产,并为未来制造治疗性蛋白质的高效生物过程奠定基础。
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Escherichia coli as a glycoprotein production host: recent developments and challenges.
- DOI:10.1016/j.copbio.2014.07.006
- 发表时间:2014-12
- 期刊:
- 影响因子:7.7
- 作者:Stephen R P Jaffé;Benjamin Strutton;Zdenko Levarski;J. Pandhal;P. Wright
- 通讯作者:Stephen R P Jaffé;Benjamin Strutton;Zdenko Levarski;J. Pandhal;P. Wright
Systematic metabolic engineering for improvement of glycosylation efficiency in Escherichia coli.
用于提高大肠杆菌糖基化效率的系统代谢工程。
- DOI:10.1016/j.bbrc.2012.02.020
- 发表时间:2012-03-16
- 期刊:
- 影响因子:3.1
- 作者:Pandhal J;Desai P;Walpole C;Doroudi L;Malyshev D;Wright PC
- 通讯作者:Wright PC
Inverse Metabolic Engineering for Enhanced Glycoprotein Production in Escherichia coli.
增强大肠杆菌糖蛋白产量的逆向代谢工程。
- DOI:10.1007/978-1-4939-2760-9_2
- 发表时间:2015
- 期刊:
- 影响因子:0
- 作者:Jaffé SR
- 通讯作者:Jaffé SR
Structural and functional characterization of NanU, a novel high-affinity sialic acid-inducible binding protein of oral and gut-dwelling Bacteroidetes species.
- DOI:10.1042/bj20131415
- 发表时间:2014-03-15
- 期刊:
- 影响因子:0
- 作者:Phansopa C;Roy S;Rafferty JB;Douglas CW;Pandhal J;Wright PC;Kelly DJ;Stafford GP
- 通讯作者:Stafford GP
Maf-dependent bacterial flagellin glycosylation occurs before chaperone binding and flagellar T3SS export.
- DOI:10.1111/mmi.12549
- 发表时间:2014-04
- 期刊:
- 影响因子:3.6
- 作者:Parker JL;Lowry RC;Couto NA;Wright PC;Stafford GP;Shaw JG
- 通讯作者:Shaw JG
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Phillip Craig Wright其他文献
Phillip Craig Wright的其他文献
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{{ truncateString('Phillip Craig Wright', 18)}}的其他基金
A new generation of E. coli expression hosts and tools for recombinant protein production
新一代大肠杆菌表达宿主和重组蛋白生产工具
- 批准号:
BB/M018172/1 - 财政年份:2015
- 资助金额:
$ 37.96万 - 项目类别:
Research Grant
A new generation of E. coli expression hosts and tools for recombinant protein production
新一代大肠杆菌表达宿主和重组蛋白生产工具
- 批准号:
BB/M018172/2 - 财政年份:2015
- 资助金额:
$ 37.96万 - 项目类别:
Research Grant
Improving biopharmaceutical production in microbial systems: Engineering GlycoPEGylation in E.coli
改善微生物系统中的生物制药生产:大肠杆菌中的工程糖聚乙二醇化
- 批准号:
BB/K011200/1 - 财政年份:2013
- 资助金额:
$ 37.96万 - 项目类别:
Research Grant
MATEs - Microbial Applications to Tissue Engineering: An Exemplar of Synthetic Biology
MATEs - 微生物在组织工程中的应用:合成生物学的范例
- 批准号:
BB/F018681/1 - 财政年份:2008
- 资助金额:
$ 37.96万 - 项目类别:
Research Grant
Silicon cell model for the central carbohydrate metabolism of the archaeon Sulfolobus solfataricus under temperature variation (P-N-01-09-23)
温度变化下古细菌硫磺菌中央碳水化合物代谢的硅细胞模型 (P-N-01-09-23)
- 批准号:
BB/F003420/1 - 财政年份:2007
- 资助金额:
$ 37.96万 - 项目类别:
Research Grant
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