Towards predictive biology: using stress responses in a bacterial pathogen to link molecular state to phenotype.

走向预测生物学：利用细菌病原体的应激反应将分子状态与表型联系起来。

• 批准号: BB/K019171/1
• 负责人: Peter Lund
• 金额: $ 40.87万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK019171%2F1
• 关键词: Towards; predictive; biology; using; stress

A "Holy Grail" in biology is to deduce how an organism will behave under different conditions (its phenotype) from knowledge of its genetic make-up and how its genes are expressed. This is not yet possible, but this proposal will move us towards this goal, using bacteria as a model system. There are several reasons why we want to be able to do this. First, we want to understand disease-causing bacteria better, so as to protect both ourselves and our food against their harmful effects better than we can do at the moment. Second, we use bacteria a lot in industry and our ability to do this will improve if we can predict in detail how they will behave under industrial conditions. Third, as biology moves towards a more synthetic approach where organisms are engineered to have specific functions, we need to understand how they will survive and thrive in different conditions. This project focusses on bacteria that cause disease, but the methods that we will develop will be applicable in many other situations. Animals, including humans, have many barriers against bacterial infection, but bacteria are resilient and adaptable and can evade some or all of these, and go on to cause disease. To understand how they are able to do this, we need to understand in much more detail the underlying biology of these organisms under the conditions that exist in our gut. Fortunately, novel methods have been devised that allow us to do this, and this proposal will apply these. For some years, we have been able to make mutations which prevent particular genes from working and use bacteria carrying these mutations to study which genes are needed for survival when bacteria are exposed to stress. We've also known how to study the way in which a particular gene is turned up or down as the external conditions change. But now, it is possible to take a very large mixture of bacteria, containing hundreds of thousands of different mutations, expose all these bacteria to many different stresses, and see how well each mutant survives each stress. This can be done in just a few experiments. We can also study how every single gene in the bacterium is responding to the stress over time, again in a few experiments. Furthermore, we can use this information to construct computer models of how all the genes which respond to the different stresses in the bacteria are connected together. This is like going from a list of addresses in a phone book to a complete map of the streets and houses in a town. The first maps that we construct using this method may not be completely correct, but we can use experiments to check the maps in detail, refining each region until it truly represents what goes on inside the bacterial cell. This is what we will do in this project. We will use the models constructed to make predictions about how bacteria will survive under different conditions, like in a particular part of the gut, and which genes will be important in helping them do this. We will specifically test our ability to make accurate predictions as part of this project. Ultimately, this should help us to predict the vulnerabilities of any pathogenic bacterium, and to use this knowledge to devise novel strategies to protect us from their potentially lethal effects.

生物学中的一个“圣杯”是从生物体的遗传组成和基因表达的知识中推断出生物体在不同条件下的行为（它的表型）。这是不可能的，但这个建议将推动我们朝着这个目标，使用细菌作为模型系统。我们希望能够做到这一点有几个原因。首先，我们希望更好地了解致病细菌，以便比目前更好地保护我们自己和我们的食物免受其有害影响。其次，我们在工业中大量使用细菌，如果我们能够详细预测它们在工业条件下的行为，我们这样做的能力将会提高。第三，随着生物学朝着更加合成的方向发展，生物体被设计成具有特定的功能，我们需要了解它们如何在不同的条件下生存和茁壮成长。这个项目的重点是引起疾病的细菌，但我们将开发的方法将适用于许多其他情况。包括人类在内的动物对细菌感染有许多屏障，但细菌具有弹性和适应性，可以逃避部分或全部这些屏障，并继续引起疾病。为了了解它们是如何做到这一点的，我们需要更详细地了解这些生物体在我们肠道中存在的条件下的潜在生物学。幸运的是，新的方法已经被设计出来，使我们能够做到这一点，这个建议将应用这些。几年来，我们已经能够使突变阻止特定的基因工作，并使用携带这些突变的细菌来研究当细菌暴露于压力时，哪些基因是生存所需的。我们还知道如何研究特定基因随着外部条件的变化而上调或下调的方式。但是现在，我们可以将含有数十万种不同突变的大量细菌混合在一起，将所有这些细菌暴露在许多不同的压力下，看看每种突变体在每种压力下的生存情况。这可以在几个实验中完成。我们还可以研究细菌中的每个基因是如何随着时间的推移对压力做出反应的，同样是在一些实验中。此外，我们可以利用这些信息来构建计算机模型，以了解细菌中对不同压力做出反应的所有基因是如何连接在一起的。这就像从电话簿中的地址列表到一个城镇的街道和房屋的完整地图。我们用这种方法构建的第一张图可能并不完全正确，但我们可以用实验来详细检查这些图，细化每个区域，直到它真正代表细菌细胞内部发生的事情。这就是我们在这个项目中要做的。我们将使用构建的模型来预测细菌在不同条件下（例如在肠道的特定部分）如何生存，以及哪些基因在帮助它们做到这一点方面很重要。作为该项目的一部分，我们将专门测试我们做出准确预测的能力。最终，这将帮助我们预测任何致病细菌的脆弱性，并利用这些知识设计新的策略来保护我们免受其潜在的致命影响。

项目成果

Mapping the Transcriptional and Fitness Landscapes of a Pathogenic E. coli Strain: The Effects of Organic Acid Stress under Aerobic and Anaerobic Conditions.

• DOI: 10.3390/genes12010053
• 发表时间: 2020-12-31
• 期刊: Genes
• 影响因子: 3.5
• 作者: Bushell F;Herbert JMJ;Sannasiddappa TH;Warren D;Turner AK;Falciani F;Lund PA
• 通讯作者: Lund PA

The Essential Genome of Escherichia coli K-12.

• DOI: 10.1128/mbio.02096-17
• 发表时间: 2018-02-20
• 期刊: mBio
• 影响因子: 6.4
• 作者: Goodall ECA;Robinson A;Johnston IG;Jabbari S;Turner KA;Cunningham AF;Lund PA;Cole JA;Henderson IR
• 通讯作者: Henderson IR

In Vitro Antibacterial Activity of Unconjugated and Conjugated Bile Salts on Staphylococcus aureus.

金黄色葡萄球菌上未缀合和共轭胆汁盐的体外抗菌活性。

• DOI: 10.3389/fmicb.2017.01581
• 发表时间: 2017
• 期刊: Frontiers in microbiology
• 影响因子: 5.2
• 作者: Sannasiddappa TH;Lund PA;Clarke SR
• 通讯作者: Clarke SR

A Bayesian Non-parametric Mixed-Effects Model of Microbial Phenotypes

微生物表型的贝叶斯非参数混合效应模型

• DOI: 10.1101/793174
• 发表时间: 2019
• 作者: Tonner P

Synergistic Impacts of Organic Acids and pH on Growth of Pseudomonas aeruginosa: A Comparison of Parametric and Bayesian Non-parametric Methods to Model Growth

• DOI: 10.3389/fmicb.2018.03196
• 发表时间: 2019-01-08
• 期刊: FRONTIERS IN MICROBIOLOGY
• 影响因子: 5.2
• 作者: Bushell, Francesca M. L.;Tunner, Peter D.;Lund, Peter A.
• 通讯作者: Lund, Peter A.