Networks of interacting genes control a variety of fundamental biological processes, including embryonic development, cell division, and cell death. Understanding the function of an entire network of genes which control development is a central problem of functional genomics and systems biology. Although general technology to solve the problem does not yet exist, it can be solved today for the network of genes which control the segmentation system of Drosophila melanogaster. The research plan to accomplish this goal is an integrated program of experimentation and computational modeling, which will be used to characterize the process by which positional information encoded in maternal gradients is transformed into precise and stable expression of the segment polarity genes engrailed and wingless in stripes one nucleus in width. This process creates an extremely precise spatial body plan from imprecise maternal cues. Early patterns containing considerable noise and variation between individuals are transformed into highly precise late patterns with little variation. The work proposed will result in a realistic and predictive theory of pattern formation and error correction in the morphogenetic field that determines Drosophila segmentation.
Our specific aims are to 1) Make use of a family of chemical kinetic models to understand the typical expression and the dynamics of the segmentation genes in wild type and mutants up the initiation of wg and en expression. 2) Exploit these models to gain deeper understanding of robustness, both in a natural context and under stress 3) Perform quantitative live imaging studies of zygotic segmentation genes, supplemented by fixed tissue data from mutants. 4.) Develop new tools to support Aims 1-3 and make them, together with all data, models, and code available to the scientific community through the FlyEx database

Public Health Relevance

This project concerns basic science with long term implications for translational science and medicine. It is concerned with the genetics of development, the scientific understanding of which is a precondition for understanding cancer and birth defects. The project also aims at a precise understanding of canalization in development, an error correction process that is closely related to wound healing and regeneration.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
Research Project (R01)
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Modeling and Analysis of Biological Systems Study Section (MABS)
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Harding, John D
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University of Chicago
Schools of Medicine
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Barr, Kenneth A; Martinez, Carlos; Moran, Jennifer R et al. (2017) Synthetic enhancer design by in silico compensatory evolution reveals flexibility and constraint in cis-regulation. BMC Syst Biol 11:116
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