The proposed work falls into three general areas. The Initial objective is to extend solved gene regulatory networks (GRNs) controlling sea urchin embryonic specification, up to gastrula stage, to encompass the whole of the embryo. This will require de novo solution for one remaining complex domain of the embryo. Following this we will build a predictive digital computational model of regulatory specification throughout the embryo from a few h after fertilization to 30h, including all interactions between domains, using the approach and software recently applied to the endomesodermal half of the embryo. A second objective is to utilize synthetic re-engineering to ascertain the logic processing functions and to answer other questions about the meaning of particular network subcircuit designs encountered in the sea urchin endomesoderm GRN. Specifically we will target double negative gate circuitry, feedback circuitry, and also redeploy differentiation gene batteries. These studies will be carried out in the context of the developing embryo, rather than in isolated """"""""toy"""""""" circuits, and will utilize combinations of recombineered BACs. Thirdly a set of collaborative proposals is presented in which the Davidson lab will work together with the McClay lab on their major objective of deciphering the control circuitry for morphogenetic functions, and the Davidson lab will work together with the Bronner lab to aid in their objective of obtaining comparative GRN analysis between cranial and trunk neural crest.
The only way medical practice will advance beyond elegant forms of bandaids and single molecule drug targets will be by interventions at the level of organization that life systems 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 Pis of this application are frequently asked by fon/vard looking members of it for collaborations, consultations, symposium presentations etc.
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