Enhancing global and mRNA specific translation for improved recombinant protein expression in in vitro cultured mammalian cells

增强整体和 mRNA 特异性翻译,以改善体外培养的哺乳动物细胞中的重组蛋白表达

基本信息

  • 批准号:
    BB/F018908/1
  • 负责人:
  • 金额:
    $ 46.84万
  • 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

项目摘要

Many of the new drugs currently under development are based upon proteins rather than traditional small molecules (e.g. antibiotics). One of the type of protein molecules that is particularly challenging to make are antibodies e.g. herceptin. These protein drugs are produced for the treatment of diseases such as cancer by cells kept in culture under defined conditions. One problem with this is that the cells we use to make proteins for therapeutic uses are not as efficient as we would like them to be and therefore we may not be able to produce enough of these drugs and the cost and demand for them is high. Protein synthesis is the process by which the information in the genetic material in the cell, DNA is converted via an intermediary substrate mRNA, into proteins. For proteins to be synthesised the mRNA must interact with a large complex called the ribosome which consists of RNAs and proteins. Ribosomes are able to decode the genetic information that is held in the mRNA and carry out the synthesis of the proteins. There are two distinct mechanisms by which mRNAs can interact with the ribosomes. The most common mechanism requires the binding of a protein complex to the 5' end of the mRNA and this complex then recruits the ribosome. However, certain mRNAs contain 5' regions that do not code for sections of proteins (termed untranslated regions; UTRs) and these sequences of RNA harbour the information that is required to form a complex RNA structure. These RNA structures allow the ribosome to be recruited to the mRNA generally a considerable distance from the 5' end and so this method of ribosome recruitment has been termed internal ribosome entry. Interestingly, messages that use internal ribosome entry generally encode proteins that are used under situations of cell stress including under temperature reduction (cold-shock). This information is of industrial relevance since the production of commercially valuable proteins (e.g. antibodies) is hindered when cells become stressed later in culture and by the cold-shock that is commonly induced during fermentation. We aim to use the 5' UTRs of mRNAs that are translationally active during cold-shock to enhance the production of proteins that are important to industry. Achieving this is very important as it is expected that with an increasing number of protein 'drugs' being developed we will lack the capability of producing large enough amounts to meet the required demand for these new drugs for the majority, as opposed to for those who can afford what must currently remain prohibitively expensive, but very effective, medicines.
目前正在开发的许多新药都是基于蛋白质而不是传统的小分子(例如抗生素)。其中一种特别具有挑战性的蛋白质分子是抗体,例如赫赛汀。这些蛋白质药物是通过在限定条件下培养的细胞生产的,用于治疗疾病如癌症。其中一个问题是,我们用来制造蛋白质用于治疗用途的细胞并不像我们希望的那样有效,因此我们可能无法生产足够的这些药物,并且对它们的成本和需求很高。蛋白质合成是细胞中遗传物质中的信息,DNA通过中间底物mRNA转化为蛋白质的过程。为了合成蛋白质,mRNA必须与一个由RNA和蛋白质组成的称为核糖体的大复合体相互作用。核糖体能够解码mRNA中保存的遗传信息并进行蛋白质的合成。mRNA与核糖体相互作用有两种不同的机制。最常见的机制需要蛋白质复合物与mRNA的5'端结合,然后该复合物募集核糖体。然而,某些mRNA含有不编码蛋白质部分的5'区域(称为非翻译区; UTR),并且这些RNA序列含有形成复杂RNA结构所需的信息。这些RNA结构允许核糖体被募集到mRNA中,通常距离5'端相当远,因此这种核糖体募集的方法被称为内部核糖体进入。有趣的是,使用内部核糖体进入的信息通常编码在细胞应激情况下使用的蛋白质,包括温度降低(冷休克)。这一信息具有工业相关性,因为当细胞在培养后期受到压力时,以及在发酵过程中通常诱导的冷休克会阻碍有商业价值的蛋白质(例如抗体)的生产。我们的目标是利用在冷休克过程中具有免疫活性的mRNA的5'UTR来增强对工业重要的蛋白质的生产。实现这一点是非常重要的,因为预计随着越来越多的蛋白质“药物”的开发,我们将缺乏生产足够大的数量来满足大多数人对这些新药的需求的能力,而不是那些能够负担得起目前仍然非常昂贵但非常有效的药物的人。

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)
Cooling-induced SUMOylation of EXOSC10 down-regulates ribosome biogenesis.
冷却诱导的exosc10的Sumoylation下调核糖体生物发生。
  • DOI:
    10.1261/rna.054411.115
  • 发表时间:
    2016-04
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Knight JR;Bastide A;Peretti D;Roobol A;Roobol J;Mallucci GR;Smales CM;Willis AE
  • 通讯作者:
    Willis AE
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Christopher Smales其他文献

Christopher Smales的其他文献

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{{ truncateString('Christopher Smales', 18)}}的其他基金

Taiwan Partnering Award: Establishing a CHO Cell Expression System for Animal Vaccine Production
台湾合作奖:建立用于动物疫苗生产的CHO细胞表达系统
  • 批准号:
    BB/T01945X/1
  • 财政年份:
    2021
  • 资助金额:
    $ 46.84万
  • 项目类别:
    Research Grant
Generation, characterisation and application of SARS-CoV-2 protein antigens for COVID-19 rapid diagnostic purposes in the hospital and community
SARS-CoV-2 蛋白抗原的生成、表征和应用,用于医院和社区中的 COVID-19 快速诊断
  • 批准号:
    BB/V011324/1
  • 财政年份:
    2020
  • 资助金额:
    $ 46.84万
  • 项目类别:
    Research Grant
An integrated cell and protein engineering approach to generate enhanced CHO cell platforms for manufacture of difficult to express biopharmaceuticals
一种集成的细胞和蛋白质工程方法,用于生成增强的 CHO 细胞平台,用于制造难以表达的生物制药
  • 批准号:
    BB/R001731/1
  • 财政年份:
    2018
  • 资助金额:
    $ 46.84万
  • 项目类别:
    Research Grant
Translation of Step-changing Bioprocesses and Expression System Technologies for Next Generation Protein Biologics Production in CHO Cells
转化用于 CHO 细胞中下一代蛋白质生物制品生产的逐步改变的生物过程和表达系统技术
  • 批准号:
    BB/N023501/1
  • 财政年份:
    2016
  • 资助金额:
    $ 46.84万
  • 项目类别:
    Research Grant
Development and Commercialisation of a Second Generation Rapid Diagnostic Test (RDT) for Human African Trypanosomiasis (HAT) and other Kinetoplastida
针对人类非洲锥虫病 (HAT) 和其他动质体的第二代快速诊断测试 (RDT) 的开发和商业化
  • 批准号:
    BB/N012496/1
  • 财政年份:
    2016
  • 资助金额:
    $ 46.84万
  • 项目类别:
    Research Grant
Feasibility study with the recombinant protein, rISG65, in a new second generation Rapid Diagnostic Test (RDT) for Sleeping Sickness
重组蛋白 rISG65 在新的第二代昏睡病快速诊断测试 (RDT) 中的可行性研究
  • 批准号:
    BB/N004434/1
  • 财政年份:
    2015
  • 资助金额:
    $ 46.84万
  • 项目类别:
    Research Grant
13 ERA IB: Investigating NOvel VAluable bio-Therapeutics and Expression systems
13 ERA IB:研究新颖有价值的生物治疗和表达系统
  • 批准号:
    BB/M000699/1
  • 财政年份:
    2014
  • 资助金额:
    $ 46.84万
  • 项目类别:
    Research Grant
FLIP Expression of recombinant target antigens for neglected tropical diseases in surrogate organisms
FLIP 在替代生物体中表达被忽视的热带病的重组靶抗原
  • 批准号:
    BB/L026279/1
  • 财政年份:
    2014
  • 资助金额:
    $ 46.84万
  • 项目类别:
    Research Grant
Bioprocessing Network: BioProNET
生物处理网络:BioProNET
  • 批准号:
    BB/L013770/1
  • 财政年份:
    2014
  • 资助金额:
    $ 46.84万
  • 项目类别:
    Research Grant
Unravelling and engineering the role of trace metals on recombinant therapeutic protein synthesis and heterogeneity from Chinese hamster ovary cells
揭示和改造微量金属对中国仓鼠卵巢细胞重组治疗性蛋白合成和异质性的作用
  • 批准号:
    BB/K017640/1
  • 财政年份:
    2013
  • 资助金额:
    $ 46.84万
  • 项目类别:
    Research Grant

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