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

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.

IL-1beta is a key mediator of inflammation, but the pathways that result in its production are complex; the aim of this proposal is to describe them quantitatively. Due to this complexity we would traditionally 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 in silicio, alone or combined, 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. To overcome the combinatorial explosion of factors involved we shall develop multi-objective evolutionary algorithms to optimise the cocktails of substances added. The result of this interdisicplinary project, combining both 'wet' and 'dry' strands in an iterative manner, 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 in order to have substantial effects on it.