Control-Theoretic Approaches in Systems Biology: sensitivity conservations as performance constraints

系统生物学中的控制理论方法：作为性能约束的灵敏度守恒

• 批准号: 261734-2012
• 负责人: Ingalls, Brian
• 金额: $ 2.04万
• 依托单位: University of Waterloo
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2012
• 资助国家: 加拿大
• 起止时间: 2012-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=505815
• 关键词: Control; Theoretic; Approaches; Systems; Biology

The proposed research addresses the 'design principles' of life. In the past, comparisons have often been made between engineered automatic feedback systems and living organisms. Recent advances in experimental techniques allow the rigorous testing of these comparisons, through the comprehensive observation of the most fundamental of biological feedback systems: biochemical and gene-regulatory networks. The proposed research addresses a particular aspect of the theory of automatic feedback systems: conservation of sensitivity. Generally, improving robustness means reducing system sensitivity -- insulating a system from unforeseen perturbations. The control engineering community has identified that in many cases, system structure imposes a conservation of sensitivity, so sensitivity reduction cannot be achieved. When this constraint is in place, the system engineer is limited to designing feedback that will redistribute sensitivity to improve system behaviour, for instance by shifting sensitivity away from components to which perturbations are dangerous. Because sensitivity in conserved, this will necessarily introduce additional sensitivity in other components. Sensitivity constraints apply in the biomolecular 'design space' as well. They have been applied to metabolic pathways in order to better understand their regulation. Recent work by myself and others indicates that these constraints are in place in a range of biochemical and genetic networks. The proposed research aims to explore where these constraints occur, and what forms they take, as well as to experimentally verify their consequences. This will result in a better understanding of cellular regulation, and thus enhance strategies that aim to alter cellular behaviour, either chemically (e.g. with drugs), or genetically (e.g. genetic engineering). These types of manipulations are key to current efforts in a range of biotechnological directions, including human health and disease, biomanufacturing, agriculture, and environmental bioremediation.

拟议的研究涉及生命的“设计原则”。 在过去，人们经常将工程自动反馈系统与生物体进行比较。 实验技术的最新进展允许通过全面观察最基本的生物反馈系统（生物化学和基因调控网络）对这些比较进行严格的测试。拟议的研究解决了自动反馈系统理论的一个特定方面：灵敏度守恒。 一般来说，提高鲁棒性意味着降低系统灵敏度--使系统免受不可预见的扰动。 控制工程界已经认识到，在许多情况下，系统结构强制要求保持灵敏度，因此无法实现灵敏度降低。 当这种约束到位时，系统工程师被限制在设计反馈，将重新分配灵敏度，以改善系统的行为，例如通过转移灵敏度远离扰动是危险的组件。 由于灵敏度是保守的，这必然会在其他组分中引入额外的灵敏度。灵敏度约束也适用于生物分子的“设计空间”。 它们已被应用于代谢途径，以更好地了解其调节。 我和其他人最近的研究表明，这些限制在一系列生物化学和遗传网络中存在。 拟议的研究旨在探索这些约束发生在哪里，它们采取什么形式，以及实验验证它们的后果。 这将导致对细胞调节的更好理解，从而增强旨在改变细胞行为的策略，无论是化学（例如药物）还是遗传（例如基因工程）。 这些类型的操作是目前在一系列生物技术方向上努力的关键，包括人类健康和疾病，生物制造，农业和环境生物修复。