Grant: Operating Grant

If you wanted to understand an electronic device like an iPod, you would likely look at the individual components, see how they are wired together and then figure out how individual and groups of components dynamically respond to inputs and what signal come out. You'd start with individual components and then look at hierarchically more complex two, three or more component relationships. Along the way, you'd make lists of motifs, groups of different components that behave the same way, to try to figure out the modular organization of the whole. Can the same logic be applied to life? In fact it can and extraordinary efforts are aimed at breaking down cellular processes in this way. But it is an arduous task and some aspects, such as dynamics are not easy to study. We have developed novel experimental strategies that allow us to both study the dynamics of regulatory circuits in cells involving genes and proteins and to dissect these circuits by disrupting, very specifically, the relationships between individual components. Further, we can perform these analyses en-masse, allowing us to obtain enough information to see if life has come up with a definable set of motifs with unique properties. The central aim of our proposal is to build on evidence for simple three component motifs that have been characterized in a model of the eukaryotic cell, that of the bakers yeast, by identifying and characterizing the behavior of these motifs. The advantage of working on yeast is that they share many genes with humans and most notably those that are most primordial and become dysfunctional with age and in diseases such as cancers. As we discuss in the proposal, we have shown how certain types of cell regulation, are particularly vulnerable to disruption of certain genes. The results of our efforts may help us to more generally define how certain cell regulation is more vulnerable to dysfunction than others and what kinds of strategies could re-stabilize them.