Molecular Mechanisms and Biochemical Circuits for Adaptation in Biological Systems

项目摘要 适应是所有生物系统最重要和最具决定性的特性之一，从单一的 从细胞到多细胞生物再到相互作用物种的种群。适应使生命系统能够适应 以应对环境的变化和压力，以维持其正常的功能。因此， 适应能力对于从人类到单个细胞的生命系统的健康和适宜性至关重要。为 在细胞水平上，在识别关键分子成分方面取得了很大进展 与适应和衡量个别系统的适应性投入产出反应有关。然而， 尽管取得了这些进展，但许多关于细胞水平适应的基本问题仍然没有得到解决。何谓 适应不同类型(化学和机械)的一般系统水平的分子机制 活细胞中的刺激物？有没有什么通用的设计原则来管理潜在的生化途径 (电路)负责细胞中各种各样的适应行为？ 在这个拟议的计划中，我们的目标是广泛地解决这些问题，以弥合分子之间的差距 相互作用和系统级别的适应行为，使用一种结合理论的综合方法 来自我们的实验合作者实验室的定量实验的分析和计算建模。 我们计划研究三个具有代表性的细胞系统：1)细菌细胞对化学信号的适应 (大肠杆菌)；2)细菌鞭毛马达对机械信号的适应；3)对气味的适应 嗅觉神经元(OSN)中的刺激。在每个系统中，我们都将开发一个系统级模型 基于已知的分子成分及其相互作用。这些系统级模型将使我们能够 针对系统级输入输出验证/证伪不同可能的分子机制(假设) 测量。通过比较这些不同系统中适应的分子机制，我们的目标是 揭示潜在的生化途径(电路)的一般特征(设计原则)，这应该 为理解其他细胞适应系统，如金属动态平衡，提供一个总体框架。 真核细胞对渗透压的反应、趋化作用以及不同类型感觉神经元的适应 感官模式。

Project Summary Adaptation is one of the most important and defining properties of all biological systems ranging from a single cell to multi-cellular organisms to populations of interacting species. Adaptation allows living systems to adjust themselves in response to environmental changes and stresses to maintain their normal functions. Therefore, the ability to adapt is crucial for the health and fitness of living systems from human to a single cell. For adaptation at the cellular level, much progresses have been made in identifying key molecular components relevant for adaptation and in measuring the adaptive input-output responses in individual systems. However, despite these advances, many fundamental questions on cellular level adaptation remain unresolved. What are the general system-level molecular mechanisms for adaptation to different types of (chemical and mechanical) stimuli in living cells? Are there any universal design principles governing the underlying biochemical pathways (circuits) that are responsible for the vast variety of adaptive behaviors in cells? In this proposed program, we aim to address these questions broadly to bridge the gap between molecular interactions and system-level adaptation behaviors by using an integrated approach that combines theoretical analysis and computational modeling with quantitative experiments from our experimental collaborators' labs. We plan to study three representative cellular systems: 1) adaptation to chemical signals in bacterium cells (Escherichia coli); 2) adaptation to mechanical signals in bacterial flagellar motor (BFM); 3) adaptation to odor stimuli in olfactory sensory neurons (OSN). In each of these systems, we will develop a system-level model based on known molecular components and their interactions. These system-level models will allow us to verify/falsify different possible molecular mechanisms (hypotheses) against the system level input-output measurements. By comparing the molecular mechanisms for adaptation in these diverse systems, we aim to uncover general features (design principles) in the underlying biochemical pathways (circuits), which should provide a general framework for understanding other cellular adaptation systems such as metal homeostasis, response to osmotic pressure, chemotaxis in Eukaryotic cells, and adaptations of sensory neurons in different sensory modalities.