COMPUTER ANALYSIS OF AGING IN DICTYOSTELIUM

本申请书中提出的研究将继续努力 定义代谢转变期间的限速事件 模式系统中的分化、衰老和死亡--网柄网柄菌 盘状骨。正在测试的假设是，对 导致分化和衰老的生化机制必须是 寻求在复杂和集成的水平上使用系统分析 比目前所考虑的任何理论所涵盖的要大得多。这个 对这一假设的最终检验是对 所构建的动力学模型。我们进展缓慢的主要原因 在理解与衰老相关的最关键变量方面 高等生物体的过程可能是：(1)我们不愿接受 涉及多个“原因”；(2)实验的广泛使用 这种材料如此复杂，以至于其基本机制和多重 所涉原因不能清楚识别，更不用说综合了；及(3) 我们无法理解和处理以下多种原因 生物有机体的条件。希望，实验性的和 本提案中概述的理论分析将作为 在高等生物体中进行类似的研究。 具体地说，我们的目标可以概括为：提交 柠檬酸循环与碳水化合物代谢成动态系统 分析和检查对这些模型的约束，例如，a) 更改特定的酶机制并确定是否模拟输出 仍然与数据一致；b)改变程度的假设 并研究其对输出的影响 对于模型；c)改变关键酶的动力学常数并重新 检查使用代谢物干扰模型的效果，例如 葡萄糖、PI和尿嘧啶；d)获得 戊糖代谢的稳态示踪模型和过渡模型 网柄网柄菌属。

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.