The research proposed in this application will continue our efforts to define rate-limiting events during the metabolic transitions essential to differentiation, aging and death in the model system, Dictyostelium discoideum. The hypothesis being tested is that an understanding of the biochemical mechanisms responsible for differentiation and aging must be sought using a SYSTEMS analysis, at a level of complexity and integration much greater than that encompassed by any theory thus far considered. The ultimate test of this hypothesis is the demonstrated predictive value of kinetic models which are constructed. We are acquiring the data necessary for the construction, testing and continued expansion of models in various areas of metabolism essential to development and aging. Specifically, we will obtain the data necessary (1) to simulate carbohydrate metabolism in the two cell types during normal differentiation and during glucose perturbation under steady-state conditions, (2) to construct a steady-state (TFLUX) and transition (METASIM) model of pentose metabolism, (3) to construct a transition model of the citric acid cycle, and (4) to construct transition models of carbohydrate metabolism in the three metabolically distinguishable cell types.
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