The fundamental questions motivating this proposal concern the physiology of gene regulation. The work is intended to elucidate the processes responsible for patterns of differential gene expression, using the embryo of the fruit fly Drosophila melanogaster as a model system. This is an experimental system where there is enough data to rigorously test proposed physiological models, and for which there is reason to believe from sequence homologies that our conclusions can be applied to other organisms, including humans. The proposed research aims to characterize the network of regulatory actions that lead to the organization of the gap and pair-rule gene expression patterns in the Drosophila blastoderm. The expression patterns of these genes undergo a refinement in spatial resolution from about fifty cell nuclei to one or two nuclei during this stage of embryonic development. There is good evidence that this is achieved by a network of regulatory interactions, but the exact nature of these interactions and how they lead to the refinement of expression patterns is not well understood. The proposed research program has four components: (1) The formulation of a mathematical model for gene regulation. (2) The acquisition of gene expression data using fluorescently tagged antibodies. (3) The determination of the correct values of the parameters in the model by numerical fits to data. The results of (1), (2), (3) will then be used (4) to validate the model by comparison to existing experimental data and by making new experimental predictions. This program of research will eventually have far reaching medical implications. Medical research has identified genes which, when mutated, cause cancer or inherited diseases. Effective treatment of these diseases will depend on a thorough understanding of how the disease is generated by genetic processes at the level of tissues and whole organisms. The proposed research will study this problem in a nonmammalian organism with a rich body of genetic information. The genetic processes that are the subject of the proposed study are well connected to those in mammals by virtue of sequence homology, and it may be that their function is essentially the same in mammals also.
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