Combinatorial Systems Biology of ROS-Regulated Interleukin-1 Gene Expression

ROS 调节的 IL-1 基因表达的组合系统生物学

• 批准号: BB/F018398/1
• 负责人: Nancy Rothwell
• 金额: $ 77.49万
• 依托单位: University of Manchester
• 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
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF018398%2F1
• 关键词: Combinatorial; Systems; Biology; ROS; Regulated

Inflammation is our bodies' response to stresses, and also helps us to heal and repair. The process of inflammation involves the coordinated actions of a large number of molecules or mediators. A molecule called interleukin-1beta, or IL-1beta for short, is key in causing inflammation. The pathways or cascade of events that result in the production of IL-1beta are complicated. Our goal is to elucidate these pathways of IL-1beta production. It is common knowledge that free radicals are, in general, harmful, and their production leads to a process called oxidative stress. So when high levels of free radicals are produced in parts of the body that are particularly sensitive such as the brain, it can be damaging to our tissues and our health. However, there is some information that shows they are important for inflammatory processes. They are also thought to be involved in the production of IL-1beta. A variety of free radicals can be produced, we know that iron ions (especially a 'free' form of iron, Fe++) can trigger the production of a particularly damaging one known as the hydroxyl radical. Molecules known as iron chelators can bind to iron and stop this from happening, while so-called antioxidants such as vitamin E can mop them up. Like any biological pathway, the process of IL-1beta production is very complicated and depends upon many factors. Due to this complexity we would normally study factors in isolation. However, biological systems are typically considerably more than the sum of their parts, and in preliminary experiments we have shown that while Vitamin E or an iron chelator ALONE do comparatively little, IN COMBINATION they have a huge effect in inhibiting the production of IL-1beta. We shall therefore construct a mathematical model of this system. The advantage of this is that we can very easily vary the rates of reactions, alone or combined, within a computer and see which combinations of changes have the greatest effect. In parallel we shall perform experimental measurements of the production of the various substances of main interest and the effect on this of these combinations. The result will be a quantitative understanding not only of the whole system but of WHY we both anticipate and find that we need to manipulate multiple steps in a biological pathway to have substantial effects on it.

炎症是我们身体对压力的反应，也能帮助我们愈合和修复。炎症过程涉及大量分子或介质的协同作用。一种叫做白细胞介素-1的分子，简称il -1，是引起炎症的关键。导致il -1 β产生的途径或级联事件是复杂的。我们的目标是阐明这些产生il -1 β的途径。众所周知，自由基通常是有害的，它们的产生会导致氧化应激过程。因此，当身体特别敏感的部位（如大脑）产生高水平的自由基时，它可能会损害我们的组织和健康。然而，有一些信息表明它们对炎症过程很重要。它们也被认为参与了il -1 β的产生。可以产生各种自由基，我们知道铁离子（尤其是铁的“自由”形式，fe++）可以引发一种特别有害的羟基自由基的产生。被称为铁螯合剂的分子可以与铁结合并阻止这种情况发生，而维生素E等所谓的抗氧化剂可以清除它们。像任何生物途径一样，il -1 β的产生过程非常复杂，取决于许多因素。由于这种复杂性，我们通常会孤立地研究这些因素。然而，生物系统通常比其各部分的总和要大得多，在初步的实验中，我们已经表明，虽然维生素E或铁螯合剂单独作用相对较小，但它们结合起来在抑制il -1 β的产生方面有巨大的作用。因此，我们将建立这个系统的数学模型。这样做的好处是，我们可以很容易地改变反应的速率，单独或联合，在计算机中，看看哪些变化的组合有最大的影响。同时，我们将对主要感兴趣的各种物质的生产以及这些组合对生产的影响进行实验测量。结果将不仅是对整个系统的定量理解，而且是对为什么我们都预期并发现我们需要操纵生物途径中的多个步骤以对其产生实质性影响的定量理解。

项目成果

Multi-compartment linear noise approximation

• DOI: 10.1088/1742-5468/2012/11/p11010
• 发表时间: 2012-11-01
• 期刊: JOURNAL OF STATISTICAL MECHANICS-THEORY AND EXPERIMENT
• 影响因子: 2.4
• 作者: Challenger, Joseph D.;McKane, Alan J.;Pahle, Juergen
• 通讯作者: Pahle, Juergen

Scientific discovery as a combinatorial optimisation problem: how best to navigate the landscape of possible experiments?

科学发现是一个组合优化问题：如何最好地浏览可能的实验的景观？

• DOI: 10.1002/bies.201100144
• 发表时间: 2012-03
• 期刊: BIOESSAYS
• 影响因子: 4
• 作者: Kell, Douglas B.

Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases.

• DOI: 10.1186/1755-8794-2-2
• 发表时间: 2009-01-08
• 期刊: BMC medical genomics
• 影响因子: 2.7
• 作者: Kell DB

Biochemical fluctuations, optimisation and the linear noise approximation.

• DOI: 10.1186/1752-0509-6-86
• 发表时间: 2012-07-17
• 期刊: BMC systems biology
• 作者: Pahle J;Challenger JD;Mendes P;McKane AJ
• 通讯作者: McKane AJ

Systematic integration of experimental data and models in systems biology.

实验数据和系统生物学模型的系统整合。

• DOI: 10.1186/1471-2105-11-582
• 发表时间: 2010-11-29
• 期刊: BMC bioinformatics
• 影响因子: 3
• 作者: Li P;Dada JO;Jameson D;Spasic I;Swainston N;Carroll K;Dunn W;Khan F;Malys N;Messiha HL;Simeonidis E;Weichart D;Winder C;Wishart J;Broomhead DS;Goble CA;Gaskell SJ;Kell DB;Westerhoff HV;Mendes P;Paton NW
• 通讯作者: Paton NW