COMPUTER ANALYSIS OF AGING IN DICTYOSTELIUM

本申请中提出的研究将继续我们的努力， 定义代谢转换过程中的限速事件， 分化，衰老和死亡的模式系统，网骨藻 盘状突 正在测试的假设是， 负责分化和衰老的生化机制必须是 寻求使用系统分析，在复杂性和集成的水平 远大于迄今为止所考虑的任何理论所包含的。 的 对这一假设的最终检验是证明的预测值， 构建的动力学模型。 我们进展缓慢的主要原因 在理解与衰老相关的最关键的变量时， 在高等生物体中的过程可能是：（1）我们不愿意接受这个事实 涉及多个“原因”;（2）实验的广泛使用 材料是如此复杂，基本机制和多个 原因不明，更谈不上整合;（3） 我们无法理解和科普多种原因， 活的有机体的条件。 希望实验性的和 本提案中概述的理论分析将作为 在高等生物中的类似研究。 具体来说，我们的目标可以概括如下： 柠檬酸循环和碳水化合物代谢是一个动态系统 分析，并检查这些模型的约束条件，例如，a） 改变特定的酶机制，并确定模型输出是否 仍然与数据一致; B）改变度的假设 并检查输出的后果 c）改变关键酶的动力学常数， 检查用代谢物干扰模型的影响，例如 d）获得用于构建包含葡萄糖、Pi和尿嘧啶的化合物的数据; 戊糖代谢稳态示踪模型和过渡模型 网骨藻

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.