Dynamic Regulation of the Cell Cycle by the Proliferation Control (Rb) and Death Control (p53) Oncogenes

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AbstractAward: DMS-0342283Principal Investigator: Paul BrazhnikThis project aims to elucidate dynamical principles and toformulate mathematical models of control mechanisms associatedwith certain genes in mammalian cells, in order to organizeavailable experimental information into a systematic,quantitative framework and to evaluate the ability of currenthypotheses to explain experimentally observed phenotypes. Inparticular, the principal investigator and collaborators willinvestigate cell proliferation control via Rb-E2F, and DNA repairand cell death control via p53-Mdm2. Models of the behavior ofthese biological modules can be tested against a substantialsupply of available experimental data, and within the models onecan test and refine ideas about mechanisms and pathways, perhapsexploring scenarios which are hard to test in real molecularbiology experiments.Mathematical methodologies useful in exploring important problemsin molecular cell biology include the theories of dynamicalsystems and bifurcation. Dynamical systems are models fornatural phenomena that change continuously with time, whilebifurcation theory studies models of phenomena that may changedramatically in an instant after evolving continuously for awhile (think of a balloon popping after it gradually inflates toan overfull state). Cellular processes regulated by particulargenes can exhibit both steady and suddenly changing behavior, andthe principal investigator and collaborators are studyingimportant cellular cycles (proliferation, plus DNA repair anddeath control) with mathematical and computational tools. Thisgrant is made under the Joint DMS/NIGMS Initiative to SupportResearch Grants in the Area of Mathematical Biology. This is ajoint competition sponsored by the Division of MathematicalSciences and the Directorate for Biological Sciences at theNational Science Foundation and the National Institute of GeneralMedical Sciences (NIGMS) at the National Institutes of Health,and the present award is funded jointly by NSF/BIO and NSF/DMS.