Grant: Operating Grant

If you wanted to understand an electronic device like an iPad, you would likely look at the individual electronic components, see how they are wired together and then figure out how individual and groups of components dynamically respond to inputs and what signals come out as a result. 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? The Nobel laureate Sir Paul Nurse recently posed this question in a commentary. He argued that we can perform this task and there are already extraordinary efforts aimed at breaking down cellular processes in this way. But cells are not built like electronic circuits. Their components work together more like a social network. To understand such a networks we need to study how key components work together as a whole while following individual relationships among them. Principally, we must study how they organize and act on each other both in space and in time. We have developed unique new technologies that allow us to achieve these aims and we propose a general strategy to study how different signals are read and compared as a cell respond to individual or different stimuli. We will perform our studies in a simple organism, bread yeast. 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.