Researchers Design a Tool to Induce Controlled Suicide in Human Cell
研究人员设计了一种用于诱导人类细胞控制性死亡的工具
ScienceDaily (Dec. 29, 2009) — When cells accumulate excessive errors in the proteins they produce, apoptosis is activated, that is to say, a cell suicide programme; however, beforehand the cells attempt to rectify the problem through a number of rescue responses. Scientists know only the general outline of the mechanisms behind cellular "stress responses," the interactions between them and the molecular components involved. Researchers at the Institute for Research in Biomedicine (IRB Barcelona) have designed a new tool to study rescue signalling pathways and cell suicide in depth.
当细胞在蛋白质生成过程中累积过量的误差时,细胞凋亡就会被启动,也就是一种细胞自杀程序,但是细胞会较早的试图通过大量的救援反应纠正出现的问题。科学家们只知道细胞“应激反应”之后的一些机制的一般概况,其中包括细胞间的相互作用和分子组成。来自巴塞罗那生物医药研究所的研究人员设计了一种新型的工具用于深入研究援救信号途径和细胞自杀。
A description of this method has been published in the last issue of the specialized Journal Nucleic Acids Research, included in the group Oxford Journals.
Journal Nucleic Acids Research在最后一期专门发表了一篇描述该方法的论文,并被牛津期刊收录。
"We have developed a strategy to induce controlled mutations in the cell, which allows us to gradually activate several repair systems that are triggered before the cell enters the cell death programme. Using previous methods, the effects on cells are less specific and may lead to parallel responses that hinder analysis of the results," explains the author of the article, Lluís Ribas de Pouplana, ICREA researcher and head of the Gene Translation Laboratory at IRB Barcelona.
巴塞罗那生物医药研究所转基因实验室负责人、ICREA研究员Lluís Ribas de Pouplana作为该篇论文的作者解释到:“我们研究了一种可以诱导细胞控制性突变的方法,这样便可以在细胞进入程序性死亡之前触发几种修复系统的逐渐激活。而以往的方法对细胞作用的特异性较差,可能会导致相似的反应而对结果分析产生干扰。
Traditional techniques consist of exposing the cells to drug or compounds that affect protein production, thereby creating instability. Renaud Geslain, a researcher in Ribas’ group and first author of the article, "had a brilliant idea to reproduce the same effect within the cell, without the help of compounds alien to the cell," recalls Ribas. Geslain manipulated a component of the cellular protein synthesis machinery that causes the production of defective proteins. "In response to the accumulation of misfolded proteins, the cellular alarm systems are switched on and stress responses are activated. Given that this approach affects all the proteins, we obtain all the reactions possible, not only responses that could be exclusive to one or a few affected proteins."
传统方法通常是将细胞暴露于药物或化合物中影响蛋白质生成,借此产生不稳定性。Ribas回忆起文章的第一作者,也就是Ribas组的一名研究员Renaud Geslain的叙述:“有一种很好的方法可以在细胞内产生类似的作用,而不需要采用外来化合物进入细胞的方式。”Geslain巧妙的处理了细胞蛋白质合成运作体系中的一种成分,从而产生了大量的缺陷型蛋白质。“当细胞积累了大量的错误折叠蛋白后,细胞的报警系统被打开,细胞应激应答被激活。通过这种方法影响所有的蛋白质,我们可以观察到所有反应,而不仅仅局限于一种或几种受影响的蛋白质。”
How to interfere with protein production?
怎样干预蛋白质生成?
Cells are bags full of proteins and all proteins are formed by large chains of amino acids. Cells continually make these molecules through a highly complex system. One of the components involved in protein production, a process in which the Gene Translation Lab is specialized, is transfer RNA (tRNA). The function of tRNA is to transport the protein synthesis machinery and the precise amino acids required for each protein under construction. Geslain designed new tRNAs, very similar to natural ones, but that place erroneous amino acids into the protein sequences under construction. "When these tRNAs are introduced, the cells starts to make and accumulate defective proteins and it reacts in response. Given that the cell still conserves the healthy proteins present before the introduction of our tRNA, we can observe the extent to which the healthy part can correct the problem. We can also see when these defects are no longer correctible and how and when cells enter the suicide programme."
细胞就像装满了蛋白质的口袋,所有的蛋白质都是由氨基酸长链构成的。细胞通过一种高度复杂的系统持续生成这些分子。转基因实验室研究的方法特异性的处理了蛋白质合成中的一种成分——转运RNA(tRNA)。tRNA的作用是运输蛋白质合成运作体系并准确转运构建蛋白质所需的氨基酸。“当引入这些处理的tRNA时,细胞便开始生产和累积缺陷型蛋白质,并且产生应激反应。鉴于细胞在引入我们的tRNA之前仍能够保存健康的蛋白质,我们可以观察到健康部位修改错误的范围,还可以观察到当这些缺陷不能再被修改时,细胞怎样以及何时进入自杀程序。”
The lab has started to obtain results using this new tool. Analyses indicate that part of the cell response to the accumulation of misfolded proteins is the production of several micro-RNAs, small molecules that regulate gene expression. "We still don’t know what they do or what genes they repress but we are discovering very surprising functional connections," notes the IRB Barcelona researcher.
该实验室采用这种新型工具进行研究得到一些结果。分析结果显示,细胞在累积错误折叠蛋白的部位产生了一些微小RNAs,是一些能够调控基因表达的小分子。巴塞罗那生物医药研究所的研究人员指出:“我们尚且不知道这些小分子的作用以及他们抑制哪些基因,但是我们发现了一些非常奇特的功能联系。”
Besides, Ribas continues, "the biological problem that we induce in the cell is directly linked to neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s, which are caused by the aggregations of misfolded proteins that cause neuronal death." The tool developed at IRB Barcelona will allow the identification of new components of the response mechanisms to these mutations. In the future, these components may become targets for intervention in these and other diseases.
他接下来指出:“我们在细胞中诱发的生物学现象与神经变性疾病有直接关系,如阿尔茨海默氏病、帕金森病和亨廷顿病,是由于错误折叠蛋白的聚集而导致的神经元死亡。”巴塞罗那生物医药研究所研制的这种工具将能够识别这些突变反应机制中的新组分。在不久的将来,这些组分可能成为上述疾病及其他一些疾病介入的新靶点。
The green fluorescent protein is produced by a system designed by researchers at IRB Barcelona and its expression demonstrates that the technique works correctly in human cells and other animal cells. (Credit: Roberto Álvarez-Medina (CSIC))
巴塞罗那生物医药研究所的研究人员设计的一种系统能够生产绿色荧光蛋白,该蛋白的表达说明了这种技术在人类细胞和其他动物细胞中都可以准确的运作。(Credit: Roberto Álvarez-Medina (CSIC))
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