The silicon trypanosome (SilicoTryp)

硅锥虫 (SilicoTryp)

• 批准号: BB/I004602/1
• 负责人: Keith Matthews
• 金额: $ 35.17万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI004602%2F1
• 关键词: silicon; trypanosome; SilicoTryp

In this proposal we intend to set the foundation for a description of the cellular workings of parasitic protozoa called trypanosomes. Trypanosomes are responsible for the disease sleeping sickness in sub-Saharan Africa. The parasites are transmitted between people by biting tsetse flies. Once injected into the bloodstream they begin to proliferate and eventually invade the brain and central nervous system. Once inside the brain the presence of parasites leads to decreasing neurological function. Patients become depressed and cognitive function breaks down. They eventually become mad, fall into a coma and die. In recent years it has become possible to dissect trypanosomes at the molecular level. We have determined the sequence of their genetic code. We can measure the abundance of the individual proteins that are assembled within the trypanosome's structure. We can also measure the manner by which chemicals are transformed from one to another within the parasite. In short, we have at our disposal the parts list that comprises a trypanosome. We would like to exploit this information to assist in designing drugs that can perturb the parasite's inner workings. However, in order to achieve this, it is not enough to have a simple parts-list of the parasite. We need to understand how those parts assemble and how they interact with one another in order to create this living system, the trypanosome. Systems Biology is a recently emerged discipline that combines high throughput measurements of cellular parts, along with measurements of the dynamics of interactions between those parts and then employs high capacity computational modelling in efforts to describe how cellular constituents combine to create recognisable biological function. An ambition of systems biology is to reconstruct biological systems from descriptions of their component pieces with mathematical descriptions that describe how those pieces interact. Increasingly, models are emerging that describe biological function emerging from combined components of the cell. For several model organisms, including yeast and the bacterium Escherichia coli, models of cellular function are being combined into a project termed 'The silicon cell' which ultimately aims to include all component pieces of a cellular system and to describe the dynamics of the connectivity between them in order to predict how the system behaves as a whole. Profiting from the availability of the full genome sequence and methods to determine how genes are turned on to produce RNA transcripts that are then translated into proteins which ultimately control the flow of life through these cells we propose to generate a 'silicon trypanosome', i.e. we propose to build fully descriptive mathemical models of the flow of information that defines a trypanosome. We will take a bottom up approach, starting with a biochemical pathway, the so-called trypanothione pathway that dictates how well trypanosomes can deal when exposed to oxidative stresses. We have chosen this pathway because a great deal is already known about biochemical parameters of the component proteins, or enzymes, of this pathway. Furthermore the trypanothione pathway links directly through the NADPH generating pentose phosphate pathway to the glycolytic pathway, which consumes the parasite's major energy supply, glucose. A comprehensive mathematical model describing the glycolytic pathway in trypanosomes already exists, hence in a bottom up manner, extending into an adjacent pathway, offers a rational way towards a comprehensive model of the trypanosome. In addition to collecting data on the component pieces of the trypanosome we will alsoimplement a range of novel mathematical techniques to ensure the models we build are testable and robust. Ultimately we aim to use the models to predict the best ways to perturb the parasite's biological make up with the hope of generating new drugs.

在此提案中，我们打算为描述称为锥虫的寄生原生动物的细胞起作用奠定基础。锥虫导致撒哈拉以南非洲的疾病疾病。寄生虫是通过咬住采摘苍蝇在人之间传播的。一旦注射到血液中，它们就开始扩散并最终侵入大脑和中枢神经系统。一旦大脑内部，寄生虫的存在会导致神经功能降低。患者变得沮丧，认知功能分解。他们最终变得生气，陷入昏迷并死亡。近年来，已经有可能在分子水平上剖析锥虫。我们已经确定了其遗传密码的顺序。我们可以测量在锥虫结构中组装的各个蛋白质的丰度。我们还可以测量化学物质在寄生虫中从一种转化为另一种的方式。简而言之，我们可以支配包括锥虫体的零件清单。我们想利用这些信息来协助设计可以扰动寄生虫内部工作的药物。但是，为了实现这一目标，只有一个简单的寄生虫列表不足。我们需要了解这些部分如何组装以及它们如何相互作用，以创建这个生物系统，即锥虫。 Systems Biology是一门最近出现的学科，结合了细胞部分的高吞吐量测量，以及对这些部分之间相互作用的动态的测量，然后采用高容量的计算建模来描述细胞成分如何结合以创建可识别的生物学功能。系统生物学的野心是通过描述这些碎片相互作用的数学描述来重建生物系统。越来越多的模型正在出现，描述了细胞组合成分的生物学功能。对于包括酵母和细菌大肠杆菌在内的几种模型生物，细胞功能的模型被合并为一个称为“硅细胞”的项目，最终旨在包括细胞系统的所有组成部分，并描述各个组成部分的连接性，并在它们是为了预测系统的整体行为。从完整基因组序列的可用性和方法中获利，以确定如何打开基因以产生RNA转录物，然后将其转化为蛋白质，这些蛋白质最终通过这些细胞来控制生命的流动，我们建议生成“硅锥虫”，即我们。建议建立定义锥体的信息流的完全描述性数学模型。我们将采取一种自下而上的方法，从生化途径开始，这是所谓的锥虫途径，该途径决定了锥虫在暴露于氧化应激时的处理方式。我们之所以选择此途径，是因为已经知道了有关该途径的组分蛋白或酶的生化参数的知识。此外，锥虫途径直接通过NADPH产生五肽磷酸盐途径连接到糖酵解途径，该糖酵解途径消耗了寄生虫的主要能量供应，即葡萄糖。描述锥虫中糖酵解途径的综合数学模型已经存在，因此以自下而上的方式延伸到相邻的途径中，为锥虫体的综合模型提供了一种理性的方式。除了收集有关锥体组件部分的数据外，我们还将体现一系列新型的数学技术，以确保我们构建的模型是可测试且可靠的。最终，我们旨在利用这些模型来预测寄生虫的生物构成的最佳方法，希望产生新药。

项目成果

Additional file 12: Figure S3. of Integrative analysis of the Trypanosoma brucei gene expression cascade predicts differential regulation of mRNA processing and unusual control of ribosomal protein expression

附加文件 12：图 S3。

• DOI: 10.6084/m9.figshare.c.3636047_d13
• 发表时间: 2016
• 作者: Antwi E

Additional file 11: Figure S2. of Integrative analysis of the Trypanosoma brucei gene expression cascade predicts differential regulation of mRNA processing and unusual control of ribosomal protein expression

附加文件 11：图 S2。

• DOI: 10.6084/m9.figshare.c.3636047_d14
• 发表时间: 2016
• 作者: Antwi E

Additional file 16: Figure S5. of Integrative analysis of the Trypanosoma brucei gene expression cascade predicts differential regulation of mRNA processing and unusual control of ribosomal protein expression

附加文件 16：图 S5。

• DOI: 10.6084/m9.figshare.c.3636047_d5
• 发表时间: 2016
• 作者: Antwi E

Integrative analysis of the Trypanosoma brucei gene expression cascade predicts differential regulation of mRNA processing and unusual control of ribosomal protein expression.

• DOI: 10.1186/s12864-016-2624-3
• 发表时间: 2016-04-26
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Antwi EB;Haanstra JR;Ramasamy G;Jensen B;Droll D;Rojas F;Minia I;Terrao M;Mercé C;Matthews K;Myler PJ;Parsons M;Clayton C
• 通讯作者: Clayton C

Additional file 20: Figure S6. of Integrative analysis of the Trypanosoma brucei gene expression cascade predicts differential regulation of mRNA processing and unusual control of ribosomal protein expression

附加文件 20：图 S6。

• DOI: 10.6084/m9.figshare.c.3636047_d4
• 发表时间: 2016
• 作者: Antwi E