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.

在这个建议中，我们打算为描述称为锥虫的寄生原生动物的细胞工作奠定基础。锥虫是撒哈拉以南非洲地区昏睡病的罪魁祸首。这种寄生虫通过叮咬采采蝇在人与人之间传播。一旦注射到血液中，它们开始增殖，并最终侵入大脑和中枢神经系统。一旦进入大脑，寄生虫的存在会导致神经功能下降。患者变得抑郁，认知功能下降。他们最终变得疯狂，陷入昏迷并死亡。近年来，在分子水平上解剖锥虫已成为可能。我们已经确定了他们的遗传密码序列。我们可以测量在锥虫结构中组装的单个蛋白质的丰度。我们还可以测量化学物质在寄生虫体内从一种转化为另一种的方式。简而言之，我们有一份包含锥虫的零件清单。我们希望利用这些信息来帮助设计能够扰乱寄生虫内部工作的药物。然而，为了实现这一点，仅仅有一个简单的寄生虫部件列表是不够的。我们需要了解这些部分是如何组装的，以及它们是如何相互作用的，以便创造出这个生命系统，锥虫。系统生物学是最近出现的一门学科，它结合了细胞部分的高通量测量，沿着这些部分之间相互作用的动态测量，然后采用高容量计算建模来描述细胞成分如何结合联合收割机以产生可识别的生物功能。系统生物学的一个目标是从描述其组成部分的数学描述中重建生物系统，描述这些部分如何相互作用。越来越多的模型出现，描述从细胞的组合成分出现的生物功能。对于几种模型生物，包括酵母和大肠杆菌，细胞功能模型正在被合并到一个名为“硅细胞”的项目中，该项目的最终目标是包括细胞系统的所有组成部分，并描述它们之间的连接动力学，以预测系统作为一个整体的行为。从全基因组序列的可用性和方法来确定基因如何被打开以产生RNA转录本，然后将其翻译成最终控制生命通过这些细胞的蛋白质，我们建议生成“硅锥虫”，即我们建议建立定义锥虫的信息流的完全描述性的生物学模型。我们将采取自下而上的方法，从生化途径开始，即所谓的锥虫硫酮途径，它决定了锥虫在暴露于氧化应激时的处理能力。我们之所以选择这一途径，是因为我们已经对这一途径的组成蛋白或酶的生化参数有了大量的了解。此外，锥虫硫酮途径通过NADPH生成戊糖磷酸途径直接连接到糖酵解途径，糖酵解途径消耗寄生虫的主要能量供应，葡萄糖。描述锥虫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，提供了一个合理的方式向锥虫的综合模型。除了收集锥虫组成部分的数据外，我们还将实施一系列新颖的数学技术，以确保我们构建的模型是可测试的和鲁棒的。最终，我们的目标是利用这些模型来预测扰乱寄生虫生物组成的最佳方法，以期产生新的药物。

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

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 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

The silicon trypanosome: a test case of iterative model extension in systems biology.

• DOI: 10.1016/b978-0-12-800143-1.00003-8
• 发表时间: 2014
• 期刊: Advances in microbial physiology
• 作者: Achcar F;Fadda A;Haanstra JR;Kerkhoven EJ;Kim DH;Leroux AE;Papamarkou T;Rojas F;Bakker BM;Barrett MP;Clayton C;Girolami M;Krauth-Siegel RL;Matthews KR;Breitling R
• 通讯作者: Breitling R