CAREER: Virtual Microbe: Biophysical Modeling of Morphogenesis

智力优势：由细胞骨架、细胞壁或细胞外环境定义的细胞形状的调节是在所有生物界的单个细胞和组织中进行的。细菌的健康、准确的生长需要细胞骨架和细胞壁合成的复杂编排来控制细胞形状并保持结构完整性，因为细菌细胞形状的变化对运动、免疫系统逃避、增殖和黏附具有关键影响。对于大多数细菌来说，细胞壁决定细胞的形状，尽管生长和形状保持的详细机制仍然难以捉摸。这项研究将产生一个通用的生物物理模型框架，在分子和细胞尺度上连接细胞形状确定的基本原理。将解决三个关键的生物学挑战：(I)细胞骨架力学和动力学与细胞壁生长的整合，(Ii)结合多层细胞壁生长来研究厚壁细菌的生长模式，以及(Iii)阐明细胞在分裂过程中如何收缩。每个项目都将询问细胞内空间组织、机械力和动力学的作用，为实验提供理论预测。总而言之，这项研究的目的是发现简单的物理规则，使细胞在王国之间实现强劲的、保持形状的生长。这种方法应该揭示细胞生长的一般物理原理，这些原理从根本上将细胞骨架的分子结构、细胞壁合成的机制以及生物体尺度行为的协调联系起来，从而解构细胞形状和组织极化的进化起源。广泛的影响：PI将建立一个维基，其中包含细菌形态发生的入门讲座，可供微生物界和世界各地的其他教育机构使用。此外，PI将分发一个用于评估细胞形状确定模型的计算平台，并将举办一次关于其实施的年度研讨会，以帮助开发其他模型。该软件还将作为一个关于弹性网络的高中教育模块的平台。该协会将继续开展小学外展、本科生和研究生教育，以及校园社区建设。PI的核心课程是细胞物理生物学，是斯坦福大学新的生物工程本科专业的基础，通过生物模型整合和激励化学、物理、数学和计算机科学。PI的微生物群落计算建模课程(在生物工程和微生物学上联合注册)将利用基于项目的学习来激励学生使用元基因组、成像和转录组数据集的计算建模，并传播他们的结果。PI将与附近一群种族和经济多元化的五年级学生合作；学生们将收集当地微生物群落的生态样本，并访问斯坦福大学，以成像他们的样本，并通过动手学习探索微生物世界。国际和平协会还通过指导本科生和研究生以及其他外联活动，向来自斯坦福大学和旧金山湾区邻近学校的贫困社会经济背景的妇女和学生展示了承诺。总的来说，这些努力将在从根本上理解细菌形态发生的未知前沿方面取得相当大的进展，并将物理学和力学与传统的微生物学方法相结合。此外，这些理论方法直接适用于合成生物学、细胞群落设计和细菌生长控制。

Intellectual Merit: Regulation of cell shape defined by a cytoskeleton, cell wall, or the extracellular environment is carried out in individual cells and tissues from all biological kingdoms. Robust, accurate bacterial growth requires sophisticated choreography of the cytoskeleton and cell-wall synthesis to control cell shape and maintain structural integrity, as changes in bacterial cell shape have critical consequences for motility, immune system evasion, proliferation, and adhesion. For most bacteria, the cell wall determines cell shape, although the detailed mechanisms of growth and shape maintenance remain elusive. This research will produce a versatile biophysical modeling framework bridging the fundamental principles of cell-shape determination at the molecular and cellular scales. Three critical biological challenges will be addressed: (i) the integration of cytoskeletal mechanics and dynamics with cell-wall growth, (ii) the incorporation of multilayered cell-wall growth to investigate the growth patterns of thick-walled bacteria, and (iii) the elucidation of how cells constrict during division. Each project will interrogate the roles of intracellular spatial organization, mechanical forces, and kinetics to provide theoretical predictions for experimentation. In total, this research aims to discover the simple physical rules that allow cells to achieve robust, shape-preserving growth across kingdoms. This approach should reveal general physical principles of cell growth that fundamentally link the molecular structure of the cytoskeleton, mechanisms of cell-wall synthesis, and the coordination of organismal-scale behavior, empowering the deconstruction of the evolutionary origin of cell shape and tissue polarity.Broader Impacts: The PI will construct a wiki containing introductory lectures on bacterial morphogenesis available to the microbiology community and other educational institutions worldwide. In addition, the PI will distribute a computational platform for evaluating models of cell-shape determination, and will run an annual workshop on its implementation to aid in development of other models. This software will also serve as a platform for a high-school educational module regarding elastic networks. The PI will continue to pursue elementary-school outreach, undergraduate and graduate education, and campus-wide community building. The PI's core class on the Physical Biology of Cells, the foundation for the new Bioengineering undergraduate major at Stanford, integrates and motivates chemistry, physics, mathematics, and computer science through biological models. The PI's class on Computational Modeling of Microbial Communities (registered jointly in Bioengineering and Microbiology) will utilize project-based learning to motivate the students to employ computational modeling of metagenomics, imaging, and transcriptomics datasets and to disseminate their results. The PI will partner with a nearby group of ethnically and economically diverse fifth graders; the students will collect ecological samples of local microbial communities and visit Stanford to image their samples and to explore the microbial world through hands-on learning. The PI has also demonstrated a commitment to women and students from underprivileged socioeconomic backgrounds, both from Stanford and from neighboring schools in the Bay Area, through mentorship of undergraduates and graduate students and other outreach activities. Collectively, these efforts will achieve considerable progress toward a fundamental understanding of the unexplored frontiers of bacterial morphogenesis and integrate physics and mechanics with traditional microbiological approaches. Moreover, these theoretical approaches have direct applicability to synthetic biology, cellular community design, and the control of bacterial growth.