Analysis of Mechanisms of Biochemical Homeostasis

生化稳态机制分析

• 批准号: 0616710
• 负责人: Michael Reed
• 金额: --
• 依托单位: Duke University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0616710&HistoricalAwards=false
• 关键词: Analysis; Mechanisms; Biochemical; Homeostasis

Cell metabolism emerges from a large, highly interconnected, hierarchical network of genetic and biochemical interactions whose behaviors depend on a great many time varying inputs. Some of these inputs induce large responses in local areas of the network and many of these local networks have been the subject of biological and mathematical investigations. Insufficient attention has been paid to fact that these local networks do not exist in isolation but are interconnected with many other such local networks in the cell. Because the global gene-biochemical network is so highly interconnected, one would expect that large changes in one local network would propagate and potentially disrupt the normal functions of other local networks. This raises challenging mathematical issues since the networks have complicated topology and the reaction dynamics are often nonlinear. The investigators will analyze how random fluctuations are attenuated in large complex networks (both random and deterministic) with homogeneous local reaction dynamics. They will also investigate the regulatory properties of specific biochemical mechanisms in small inhomogeneous networks that stabilize particular concentrations and fluxes against outside perturbations. The research builds on previous work of the investigators who discovered a range of novel regulatory mechanisms that produce homeostasis in one-carbon metabolism. The properties of cells depend on a large, highly interconnected, hierarchical network of genetic and biochemical interactions. These networks do not exist in isolation but are interconnected with many other such networks in the cell. Because the global gene-biochemical network is so highly interconnected, one would expect that large changes in one location would propagate and disrupt the normal functions at other locations. We will develop a mathematical theory of how disturbances propagate through large biochemical networks. We will apply the theory to increase our understanding of the structure and function of the folate and methionine cycles, which are important parts of cell metabolism. Defects in the folate and methionine cycles are associated with cancer and many developmental abnormalities. We expect that the mathematical theory will be broadly applicable to other biochemical and gene networks and to many other complex biological systems, such as neurobiology and ecology. Interdisciplinary training of undergraduate students, graduate students, and a postdoctoral fellow is a central part of the research project.

细胞代谢来自遗传和生化相互作用的大型，高度相互连接的分层网络，其行为取决于很多时间变化的输入。 这些输入中的一些引起了网络本地地区的大量反应，其中许多本地网络都是生物学和数学研究的主题。 事实上，这些本地网络并非孤立地存在，而是与单元格中许多其他此类本地网络相互联系的事实，没有足够的关注。 由于全球基因生物化学网络是如此高度互连，因此人们希望一个本地网络的大型变化会传播并可能破坏其他本地网络的正常功能。 由于网络具有复杂的拓扑结构，并且反应动态通常是非线性的，因此这引发了具有挑战性的数学问题。 研究人员将分析如何通过均匀的局部反应动力学在大型复杂网络（随机和确定性）中减弱随机波动。 他们还将研究小型不均匀网络中特定生化机制的调节性质，这些机制稳定了针对外部扰动的特定浓度和通量。这项研究基于研究人员的先前工作，他们发现了一系列新型的调节机制，这些机制在单碳代谢中产生稳态。细胞的特性取决于遗传和生化相互作用的大型，高度相互联系的分层网络。 这些网络不是孤立存在的，而是与单元格中许多其他此类网络互连的。 由于全球基因生物化学网络是如此高度互连，因此人们希望一个位置的大变化会在其他位置传播并破坏正常功能。 我们将发展一个数学理论，即干扰如何通过大型生化网络传播。 我们将运用该理论来增加对叶酸和蛋氨酸循环的结构和功能的理解，这是细胞代谢的重要部分。 叶酸和蛋氨酸周期的缺陷与癌症和许多发育异常有关。 我们预计数学理论将广泛适用于其他生化和基因网络，以及许多其他复杂的生物系统，例如神经生物学和生态学。 对本科生，研究生和博士后研究员的跨学科培训是研究项目的中心部分。