CAREER: Stochastic Effects in the Microbial Cell Cycle: From Single-cell Level Variability to Population Growth

该项目侧重于微生物（如细菌）以稳健和有效的方式调节细胞周期中各种细胞过程的机制的数学和生物物理建模，重点关注DNA复制，分裂和蛋白质生产的耦合。该团队将建立数学模型，阐明描述微生物生长的规律，以及大小调节、细胞周期进程和蛋白质生产之间的相互作用。此外，还将研究单细胞变异对整个种群生长的影响。模型预测将用于设计新的实验，并将由合作者进行测试。在PI十多年丰富的外联经验的基础上，PI建议发展三个重要的教育项目，每个项目针对不同的目标受众。首先，PI将继续并扩大他对“教学”计划的支持，为一个项目开发新的内容，该项目将使剑桥大学种族多样化的K-12社区接触到STEM内容，特别是生命系统的物理学。在这个项目中，PI和他的团队将直接与数百名来自剑桥公共系统的七年级学生互动，让他们接触学术生活和现代科学。其次，PI将与哈佛自然历史博物馆合作，并将在一个名为“微生物生命：视线边缘的宇宙”的新展览中发挥作用，他将在那里向K-12教师展示。第三，PI将为波士顿地区的高中生制定一个物理奥林匹克指导计划，特别强调女学生和来自代表性不足群体的学生。总之，这些项目将使大量的学生和教师接触到学校课程中没有涉及的令人兴奋的话题，并将旨在吸引学生从事科学和研究。该项目涉及微生物细胞周期的数学建模，重点关注DNA复制、细胞分裂和蛋白质生产的调节和耦合。这些是所有生命形式共同的基本过程。提出的方法之一是使用朗格万型方程来产生细胞周期的粗粒度描述。事实证明，这种现象学模型在细胞生理学研究中非常有用，可以为我们提供对生物过程的重要见解。生物系统中强反馈的存在，以及各种随机性的来源，导致了重大的理论挑战，这将在本提案中得到解决和发展。同样，对人口增长的研究涉及处理谱系树中细胞之间的微妙关系，这是一个长期存在的、具有数学挑战性的问题。除了这些技术上的困难之外，还有一个更深刻的问题：选择“正确的”最小模型，既能捕捉到现象的本质，又具有预测能力。加深我们对细胞周期的基本理解将直接体现在广泛的问题上。开发新的抗生素将有助于提高对细菌细胞周期的理解，以及对单细胞变异对种群增长的影响的拟议研究。特别是，分枝杆菌的生长和细胞周期是一个未被充分探索和了解的问题，它的进展对结核分枝杆菌的治疗有重大影响。同样，研究单细胞微生物的细胞周期将使我们能够在单细胞水平上解决它，而不需要额外的细胞-细胞信号传导的复杂性，这将为我们提供可能推广到哺乳动物组织的生长调节及其在癌症生长过程中的失败的重要见解。物理学、数学、工程学和生物学之间的重要联系似乎很有希望，并将成为这项研究计划的核心。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This project focuses on mathematical and biophysical modeling of the mechanisms through which microorganisms such as bacteria regulate the various cellular processes in the cell cycle in a robust and efficient way, focusing on the coupling of DNA replication, division and protein production. The team will construct mathematical models that will elucidate the laws describing microbial growth, and the interplay between size regulation, cell cycle progression and protein production. Moreover, the implications of single-cell variability on the growth of the population as a whole will be studied. Model predictions will be used to design new experiments and will be tested by collaborators. Building on the PI's rich experience in outreach for more than a decade, the PI proposes to develop three important educational programs, each aimed at a different target audience. First, the PI will continue and extend his support to the "Teach" initiative, developing new content for a program which exposes the ethnically diverse K-12 community in Cambridge to STEM content, and in particular the physics of living systems. Within this project, the PI and his group will interact directly with hundreds of seventh graders from the Cambridge public system, exposing them to academic life and to modern science. Second, the PI will collaboration with Harvard's Museum of Natural History, and will take a role in a new exhibit on "Microbial Life: A Universe at the Edge of Sight", where he will present to K-12 teachers. Third, the PI will develop a mentoring program for the Physics Olympiad for high school students in the Boston area, putting special emphasis on female students and students from underrepresented groups. Together, these projects will expose a large number of students and teachers to exciting topics which are not covered in their school curriculum, and will aim at attracting the students into science and research.The project deals with mathematical modeling of the cell cycle in microbes, focusing on the regulation and coupling of DNA replication, cell division and protein production. These are fundamental processes common to all life forms. One of the proposed approaches is to use Langevin-type equations to produce coarse-grained descriptions of the cell cycle. Such phenomenological models have proven to be extremely useful in the study of cell physiology, and can provide us with important insights into the biological processes. The existence of strong feedback in biological systems, in addition to various sources of stochasticity, leads to significant theoretical challenges, which will be addressed and developed within this proposal. Similarly, the study of population growth involves dealing with subtle correlations between cells in a lineage tree, which is a long-standing, mathematically challenging problem. To these technical difficulties is added to one of a more profound nature: choosing the "correct" minimal model that can capture the essence of the phenomena and yet have predictive power. Deepening our fundamental understanding of the cell cycle will have direct manifestations on a broad spectrum of problems. Developing novel antibiotics will be aided by an improved understanding of the bacterial cell cycle, as well as the proposed study of the effects of single-cell variability on the population growth. In particular, the growth and cell cycle of mycobacteria is an underexplored and poorly understood problem, its advance having significant impact on treatment of M. tuberculosis. Similarly, studying the cell cycle in single-celled microbes will allow us to resolve it at the single-cell level, without the added complication of cell-cell signaling, which will provide us with important insights that might be generalized to growth regulation in mammalian tissues, and its failure during cancer growth. The non-trivial connections between physics, mathematics, engineering and biology appear to hold much promise and will lie at the heart of this research program.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.