Control of cellular resource allocation across biological scales in microorganisms

项目摘要 动态平衡是所有细胞生理控制的基本特征。在过去的fiVe年里，一个新的 我们共同发现的动态平衡原理正在改变我们对细胞大小控制的看法。这个原则， 被称为“加法器”，规定细胞在出生和分裂之间增加fi固定大小，而不考虑细胞大小在 出生。因此，加法器原理由于其被动的性质而有别于许多生物控制，因为 类似加法器的单元在以下情况下不使用任何明显的大小感知或反馈机制来触发除法 它们达到了fiX的临界大小。拟议的计划是我们在细胞大小控制方面成功的延伸 研究以了解更广泛的生理控制类别。 首先，我们将研究生理过程的精确性和稳健性的机制。 我们将重点关注细菌中的复制启动，因为它可以作为一个易于处理的模型来解决这些长期的 长期存在的问题。生理控制的另一个重要方面是细胞如何将其资源分配给 成长。目前基于大肠杆菌的范例是，细胞平衡氨基酸的供需，以 在所有增长条件下最大限度地提高增长率。这些模型很重要，因为它们已经能够 为了解释细胞能量的产生与蛋白质的产生之间的Tradeoff 癌症。然而，我们已经在枯草杆菌中获得了直接挑战以大肠杆菌为中心的实验结果。 增长控制的观点。因此，我们将寻求更一般的蜂窝资源分配原则 包括大肠杆菌和枯草杆菌，理想情况下超越细菌。最后，我们将扩展我们以前的工作 关于细胞大小的控制，以研究细胞如何在蛋白质和细胞器 不对称的分割，这在遗传和细胞老化的背景下很重要。 这些问题需要从生理学到新技术开发的多学科方法。 为此，我们将与在其研究fi领域处于领先地位的合作者合作。此外，在一段时间内， 十年来，我们一直在做出重大的ff努力，向研究界普及技术。我们预计 从我们提议的研究中产生的知识和技术将开启令人兴奋的新 为生理学和细胞生物学的其他重要发现提供研究途径和便利。

Project Summary Homeostasis is a fundamental feature of physiological control in all cells. In the past five years, a new homeostatic principle co-discovered by us has been changing our view of cell-size control. This principle, known as the “adder”, states that cells add fixed size between birth and division irrespective of the cell size at birth. The adder principle is therefore distinct from many biological controls due to its passive nature, as the adder-like cells do not employ any apparent size sensing or feedback mechanisms to trigger division when they reach a fixed critical size. The proposed program is an extension of our success in cell-size control research to understand a broader class of physiological controls. First, we will study the mechanisms responsible for the precision and robustness of physiological processes. We will focus on replication initiation in bacteria as it can serve as a tractable model to solve these long- standing problems. Another important aspect of physiological control is how cells allocate their resources to growth. The current paradigm based on E. coli is that cells balance supply and demand of amino acids to maximize growth rate under all growth conditions. These models are important because they have been able to explain the tradeoff between production of cellular energy vs. production of proteins that is pertinent to cancer. However, we have obtained experimental results in B. subtilis that directly challenged this E. coli centric view of growth control. We will thus seek more general principles of cellular resource allocation that encompass both E. coli and B. subtilis, and ideally beyond bacteria. Finally, we will extend our previous work on cell-size control to investigate how cells ensure physiological equilibrium when proteins and organelles partition asymmetrically, which is important in the context of inheritance and cellular aging. These questions require multidisciplinary approaches from physiology to development of novel technologies. To this end, we will work with collaborators who are leaders in their research fields. Furthermore, over a decade we have been making major efforts to democratize technologies to the research community. We expect the knowledge and technology that will be generated from our proposed research to open exciting new research avenues and facilitate other important discoveries in physiology and cell biology.