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. Major reasons for our slow progress in understanding the most critical variables associated with the aging process in higher organisms may be: (1) Our reluctance to accept the fact that multiple """"""""causes"""""""" are involved; (2) the widespread use of experimental material which is so complicated that the basic mechanisms and multiple causes involved cannot be clearly recognized, much less integrated; and (3) our inability to understand and cope with a multiplicity of causes under the conditions of the living organism. Hopefully, the experimental and theoretical analyses outlined in this proposal will serve as a model for similar studies in higher organisms. Specifically, our goals may be summarized as follows: Submit the models of the citric acid cycle and carbohydrate metabolism to a dynamic systems analysis, and examine the constraints on these models, for example, a) change specific enzyme mechanisms and determine whether or not model output is still consistent with the data; b) change the assumption of the degree of compartmentation in mitochondria and examine the consequences on output for the model; c) change kinetic constants of critical enzymes and re- examine the effects of perturbing the model with metabolites such as glucose, Pi, and uracil; d) obtain the data for the construction of a steady state tracer model and a transition model of pentose metabolism in Dictyostelium.
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