INSPIRE: Molecular Underpinnings of Bacterial Decision-Making

INSPIRE：细菌决策的分子基础

• 批准号: 1241332
• 负责人: Jose Onuchic
• 金额: $ 100万
• 依托单位: William Marsh Rice University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2018-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1241332&HistoricalAwards=false
• 关键词: INSPIRE; Molecular; Underpinnings; Bacterial; Decision

This CREATIV award is partially funded by the Biomolecular Dynamics, Structure and Function and the Networks and Regulation Clusters in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences; the Physics of Living Systems Program in the Division of Physics, the Condensed Matter and Materials Theory Program in the Division of Materials Research, and the Chemistry of Life Processes Program in the Division of Chemistry in the Directorate of Mathematical and Physical Sciences. The objective of this CREATIV project is to investigate the fundamental question of how intricate protein-based molecular machines can determine cellular-level dynamics for living systems. Specifically, the goal is to create a framework for quantitatively predicting functional consequences of designed changes in protein systems. This project will focus on the decision-making circuitry in Bacillus subtilis as a test case for the thesis that, although biology starts from the molecular scale, it is only at the cellular and multicellular scales that one sees life in action, as a distinct form of matter having goal oriented behavior. This is the level at which evolutionary selective pressures operate. It therefore must be the case that the dynamics at these higher-scales are directly determined by their molecular underpinnings. Exactly how this works has not yet been understood even for simple forms of life such as bacteria. Instead, quantitative systems-biology approaches today remain impoverished of molecular detail and one cannot hope for an understanding of either why things work the way they do, or, often more importantly, how we can intervene at the molecular scale to engineer the system performance. The PIs and their collaborators will apply an integrative approach that combines computational and experimental techniques to bridge this huge gap in our understanding and predictive capability of the quantitative functionality of biological systems. Recent progress on the Bacillus system has for the first time enabled this type of trans-scale approach. At the molecular level, advances in modeling and new ideas utilizing sequence-based data can effectively treat protein-protein interactions and conformational changes associated with chemical function. Cellular-level circuits that govern sporulation and competence have been the subject of much recent interest and there is in place an initial set of ideas regarding the logic implemented therein. Finally, the coupling between each cell's decision-making in overall colony structure is being vigorously studied. This research project is inherently multidisciplinary, combining protein chemistry with signal transduction, combining molecular biology and biophysics with complex pattern-formation physics, and combining non-equilibrium statistical mechanics with synthetic biology. This work is high risk and potentially high pay off. Molecular modelers have stayed away from making predictions as to how specific changes will be manifested at the scale of life, as this was considered to be too hard as compared to explaining in vitro biochemistry data. The results from this project would be transformative, changing how we approach the quantitative analysis of integrated biological systems. It is therefore highly appropriate for the NSF CREATIV program. The basic knowledge generated from this CREATIV project will be crucial for revolutionizing our ability to control biofilms by molecular manipulation. Biofilm control is crucial for bacteria-based environmental remediation and for modern desalination. This project will provide a fertile ground to expose junior scientists to the challenge of cross-disciplinary research, both theoretical and experimental, which explicitly aims to break down the barriers between different subfields. This will lead to a future workforce better able to face the challenges of modern quantitative biology. Finally, bacterial colony structures and their cellular and molecular underpinnings are a fascinating area with which one can draw the public into contact with the ideas of modern science.

CREATIV奖的部分资金来自生物科学局分子和细胞生物科学部的生物分子动力学、结构和功能以及网络和调控簇；物理部的生命系统物理学计划，材料研究部的凝聚态物质和材料理论计划，以及数学和物理科学局化学部的生命过程化学计划。CREATIV项目的目标是研究复杂的基于蛋白质的分子机器如何确定生命系统的细胞水平动力学这一基本问题。具体地说，目标是创建一个框架，用于定量预测蛋白质系统中设计的变化的功能后果。这个项目将重点放在枯草芽孢杆菌中的决策电路上，作为论文的测试案例，尽管生物学始于分子尺度，但只有在细胞和多细胞尺度上，人们才能看到生命的行动，作为一种具有目标导向行为的独特形式的物质。这是进化选择压力发挥作用的水平。因此，这些较高尺度上的动力学必然是由它们的分子基础直接决定的。即使对于细菌等简单的生命形式，这一过程的确切机制也尚不清楚。取而代之的是，今天的定量系统生物学方法仍然缺乏分子细节，人们不能指望理解事物为什么以它们的方式工作，或者更重要的是，我们如何在分子尺度上进行干预以设计系统性能。PI和他们的合作者将应用一种结合计算和实验技术的综合方法，以弥合我们对生物系统定量功能的理解和预测能力方面的巨大差距。芽孢杆菌系统的最新进展首次使这种跨规模的方法成为可能。在分子水平上，模型的进步和利用基于序列的数据的新想法可以有效地处理蛋白质-蛋白质相互作用和与化学功能相关的构象变化。控制孢子形成和能力的细胞水平回路一直是最近感兴趣的主题，关于其中实现的逻辑已经有了一套初步的想法。最后，对群体整体结构中各细胞决策之间的耦合问题进行了深入研究。这一研究项目本质上是多学科的，将蛋白质化学与信号转导相结合，将分子生物学和生物物理学与复杂模式形成物理相结合，将非平衡统计力学与合成生物学相结合。这项工作风险很高，回报也可能很高。分子模型师一直没有预测具体的变化将如何在生命的规模上表现出来，因为与解释体外生物化学数据相比，这被认为太难了。这个项目的结果将是变革性的，改变我们处理集成生物系统的定量分析的方式。因此，它非常适合NSF CREATIV计划。CREATIV项目产生的基本知识将对我们通过分子操作控制生物膜的能力产生革命性的影响。生物膜控制对于基于细菌的环境修复和现代海水淡化至关重要。该项目将提供肥沃的土壤，让初级科学家接受跨学科研究的挑战，包括理论和实验研究，其明确目标是打破不同子领域之间的障碍。这将导致未来的劳动力能够更好地面对现代数量生物学的挑战。最后，细菌菌落结构及其细胞和分子基础是一个引人入胜的领域，人们可以通过它吸引公众接触现代科学的思想。