This is an application for renewal of a Program Project now in its 14'^ year. Here we propose to build in novel directions on the large success we have had in solving and authenticating gene regulatory networks (GRN) for development. GRNs provide causal explanations for developmental processes in the terms of the genomic regulatory code, in which all species-specific developmental processes are ultimately programmed. A developmental GRN serves as a conceptual, system-level logic map, which we have shown to possess direct predictive power. Thus GRNs bridge between functional genomic DNA sequence of regulatory significance and the biology of embryogenesis and body plan formation. They do this by specifying the regulatory interactions which causally drive the progression of regulatory states in diverse cellular territories. During recent years, this Program has been responsible for the experimental solution of the most advanced developmental GRN yet available for any developing animal organism. This is the GRN underlying the specification of the endomesodermal territories of the sea urchin embryo. Recently proof of the principle that as a GRN approaches completion it indeed provides explanation of all the observed biological, functions has been obtained in this work. We now intend to capitalize on the growing suite of successful technological and conceptual approaches to GRN analysis that we have developed, to confront challenges that heretofore were inaccessible, or could not even have been defined. Current or soon to be completed sea urchin embryo GRNs include all but one of the major domains of the embryo, from the earliest zygotic genomic activity (at the beginning of cleavage) to just before gastrulation. In addition, in the current period of the Program Project, an advanced GRN has been successfully constructed for the cranial neural crest of the chicken using the intellectual and technological approaches pioneered by this Program Project. The DAVIDSON COMPONENT (Project I) of the sea urchin embryo GRN will now expand GRN analysis to Include the whole of the embryo in a single GRN model such that every input to every part of RENEWAL The only way medical practice will advance beyond elegant forms of band aids and single molecule drug targets will be by interventions at the level of organization that life system actually operate, particularly the control systems. This Project concerns the most advanced example of genomic control systems biology we have at present. Its successful conclusion will show what the structure of these systems is;how to think about intervening in them;and directly inform considerations of the role of developmentally active regulatory gene mutations in the many forms of human developmental genetic disease we have become aware of. The medical research community is well aware of these points and the PI's of this application are frequently asked by forward looking members of it for collaborations, consultations, symposium presentations etc.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1-DSR-Z (ED))
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Coulombe, James N
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California Institute of Technology
Schools of Arts and Sciences
United States
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