Gauging how the plasticity of cellular organizations dictates growth, death and adaptation in single bacterial cells

项目摘要/摘要 细菌在不同的环境中经历戏剧性的细胞重组。理解非遗传性， 细胞组织的可逆可塑性是解开全细胞水平生存算法的关键， 细菌的生长、适应和感染，在对抗能够 适应各种利基环境，并能耐受人体内的抗生素。蜂窝空间令人难以置信地拥挤着 生物分子却组织得很好。然而，我们仍然缺乏对细胞空间的精确理解 有组织地决定细胞尺度的行为、生理和健康。我实验室的长期目标是 描述细胞尺度上的生命如何从生物分子及其相互作用中产生的基本原理。在……里面 在接下来的五年里，我们将通过评估蜂窝组织的主要功能如何互连来实现这一目标 在细菌细胞中的生理状态和适合性，在模型生物中，如大肠杆菌和人类 病原体，如铜绿假单胞菌。 细胞的组织通过物理、化学和化学的组合连接到它的生理状态 生物过程。我们将尝试通过检验两个基本假设来解开这一复杂性 我们的初步观察表明：(1)膜房地产假说--细胞质 膜上充满了蛋白质，细胞需要微调密度、组成和 优化细胞适合性的膜蛋白的组织，以及(2)细胞过剩假说-- 核心生物合成机器的过量不利于稳定增长，反而有利于稳定增长。 有利于适应新环境。为了更好地测试这些想法，我们将量化并操纵 膜蛋白的密度、组成和空间组织以及核心生物合成的丰度 并检查它们对生理状态的影响，如生长、适应和细胞死亡。我们会 使用这些结果来测试物理模型，这些模型通过与 膜物理和操作物理的理论家。这些任务需要具备以下两个方面的专业知识 实验和建模。我们实验室在生物物理、生物工程和分子生物学方面的经验将 美国在进行研究和促进跨领域合作和互动方面具有独特的地位。我们也 计划发布和共享将在整个研究过程中产生的新工具和数据集，并与科学 社区，如微流控设备、图像分析软件和蛋白质物理数据库 属性。无论这些假设是否会得到证实，这些项目的结果都可以帮助我们在细胞之间架起桥梁 组织和生理学，并更好地了解细胞适应，这是一门可以 扩展到研究其他高等生物。

Project Summary/Abstract Bacteria undergo dramatic cellular re-organizations in different environments. Understanding the non-genetic, reversible plasticity of cellular organization is crucial to unraveling the whole-cell level algorithm of survival, growth, adaptation, and infection of bacteria, with biomedical significance in combating pathogens that can adapt to various niches and tolerate antibiotics in the human body. Cellular space is incredibly crowded with biomolecules yet well-organized. However, we still lack a precise understanding of how cellular space is organized to dictate cellular scale behaviors, physiology, and fitness. The long-term goal of my lab is to delineate basic principles of how life at the cellular scale emerges from biomolecules and their interactions. In the next five years, we will pursue this goal by gauging how key features of cellular organizations interconnect with physiological states and fitness in bacterial cells, in model organisms such as E. coli, and human pathogens such as P. aeruginosa. The organization of the cell connects to its physiological state via a combination of physical, chemical, and biological processes. We will try to disentangle this complexity by testing two fundamental hypotheses suggested by our preliminary observations: (1) the membrane real-estate hypothesis – the cytoplasmic membrane is so packed with proteins that the cell needs to fine-tune the density, composition, and organization of the membrane proteins for optimizing cell fitness, and (2) the cellular surplus hypothesis – the core biosynthetic machines have an excess amount that does not benefit steady-state growth, but rather is beneficial for adaptation to a new environment. To better test these ideas, we will quantify and manipulate the density, composition, and spatial organization of membrane proteins and the abundance of core biosynthetic machines and examine their effects on physiological states such as growth, adaptation, and cell death. We will use these results to test physical models that render possible optimality principles by collaborating with theorists in membrane physics and operations physics. These tasks require expertise in both quantitative experiments and modeling. Our lab’s experience in biophysics, bioengineering, and molecular biology will set us in a unique position to perform the research and foster cross-field collaborations and interactions. We also plan to publish and share new tools and datasets to be yielded throughout the research with the scientific community, such as microfluidic devices, image analysis software, and databases of protein physical properties. Whether these hypotheses will be verified, outcomes from these projects can help us bridge cellular organization and physiology and understand better cellular adaptation, a branch of knowledge that can be extended to studying other higher organisms.