Current descriptions of gene regulatory circuits emphasize the causal pathways and networks by which the molecules in the system interact and function. In general, however, these models do not predict in detail the behavior of the system. Complex regulatory systems have """"""""emergent"""""""" behavior that arises from interactions among their components. This behavior, often termed """"""""system behavior,"""""""" is difficult to predict due to factors such as feedback and non-linearity. The purpose of this application is to examine and characterize the system behavior of a gene regulatory circuit that is well-understood at the mechanistic level, E. coli bacteriophage lambda. The lambda circuitry can exist in either of two alternative stable regulatory states, the 1ysogenic and lytic states, and can switch between these states during the process of prophage induction. It is proposed to characterize three aspects of system behavior in this circuitry: Robustness, which is a measure of how much the components can change without disrupting system behavior, stability, or the tendency of a system in a stable state to remain in that state; and threshold behavior, which describes the property that the system switches its state in response to input only above a critical set-point. Each of these behaviors will be characterized by isolating mutants that affect the components of the system, or that alter the behavior. Mutant forms of the circuitry will be analyzed for their effects on all aspects of the behavior. ln addition, altered forms of the circuit will be isolated and characterized. Finally, new forms of the lambda circuitry will be designed using components from other sources. These studies should provide insight into mechanisms by which complex circuits can evolve, and should lay the groundwork for design of regulatory circuits. One potential application is that circuits could be designed to be specifically responsive to drugs without crosstalk with other signalling systems, and hence could be used to treat disease.
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