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调节是在所有生物王国的单个细胞和组织中进行的。强健、准确的细菌生长需要复杂的细胞骨架和细胞壁合成，以控制细胞形状和保持结构完整性，因为细菌细胞形状的变化对运动、免疫系统逃避、增殖和粘附具有关键影响。对于大多数细菌来说，细胞壁决定了细胞的形状，尽管生长和形状维持的详细机制仍然难以捉摸。这项研究将产生一个多功能的生物物理建模框架，在分子和细胞尺度上连接细胞形状测定的基本原理。将解决三个关键的生物学挑战：(i)将细胞骨架力学和动力学与细胞壁生长结合起来，（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。总的来说，这项研究的目的是发现简单的物理规则，使细胞能够实现健壮的、保持形状的跨界生长。这种方法将揭示细胞生长的一般物理原理，从根本上联系细胞骨架的分子结构、细胞壁合成机制和有机体尺度行为的协调，从而解构细胞形状和组织极性的进化起源。更广泛的影响：PI将建立一个包含细菌形态发生入门讲座的wiki，供微生物界和全球其他教育机构使用。此外，PI将分发一个计算平台，用于评估细胞形状确定模型，并将举办一个关于其实施的年度研讨会，以帮助开发其他模型。该软件还将作为高中弹性网络教育模块的平台。PI将继续开展小学外展、本科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，这是斯坦福大学新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（生物工程和微生物学联合注册）将利用基于项目的学习来激励学生使用宏基因组学、成像和转录组学数据集的计算建模，并传播他们的结果。PI将与附近一群不同种族和经济背景的五年级学生合作；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，对他们的样本进行成像，并通过实践学习探索微生物世界。该计划还通过指导本科生和研究生以及其他拓展活动，向来自斯坦福大学和湾区邻近学校的贫困社会经济背景的女性和学生展示了自己的承诺。总的来说，这些努力将在对细菌形态发生尚未探索的前沿的基本理解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，这些理论方法对合成生物学、细胞群落设计和细菌生长控制具有直接的适用性。

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.