Building a Proportional Cell: Statistical Physics of Subcellular Size Control

材料研究部、分子与细胞生物科学部和物理部为该奖项提供资金。该奖项支持细胞生物学基础问题的理论研究和教育，并对生物材料和统计物理学产生影响。所有活细胞的一个显著特征是它们包含许多被称为细胞器的亚细胞部分，它们执行不同的功能。细胞器有不同的大小和形状，这些物理属性通常与它们的功能密切相关。例如，线粒体是充满脂质膜的室室，脂质膜折叠多次。大膜支持嵌入膜中的蛋白质机器，其功能是制造细胞燃料分子。类似地，细胞也会构建长度与细胞大小精确匹配的长聚合物电缆，用于将材料从细胞的一边输送到另一边。这些观察结果引发了一个问题：细胞是如何组装这样的三维结构的？虽然细胞DNA中编码的基因携带着制造分子构建块所需的信息，但它们是如何自我组装成复杂而有功能的三维结构的，在很大程度上仍然是未知的。PI将使用亚细胞结构组装的数学模型来考虑这些基本问题。这些模型将根据几个合作生物学实验室获得的实验数据进行测试。目标将是确定通用设计原则的组装，导致一个明确的大小和形状的亚细胞结构。在细胞中进行的新实验将会激发出潜在的有用见解，用于制造能够自组装成特定形状和尺寸的合成材料。该研究的跨学科性质将为物理专业的学生提供从事前沿生物学研究的机会。它将为他们提供必要的技能，成为由生物学家和物理学家组成的跨学科研究团队的有效成员。这些技能对于未来的科学、技术、工程和数学工作者尤为重要，因为社会面临的大多数重大问题都需要来自不同学科的科学家共同努力。技术概述材料研究部、分子和细胞生物科学部和物理部为该奖项提供资金。该奖项支持细胞生物学基础问题的理论研究和教育，并对生物材料和统计物理学产生影响。细胞中的亚细胞结构已经被观察了数百年，但直到最近，我们才开发出实验工具来解决有关它们的关键问题，例如：细胞器是如何获得其特定形状的？细胞如何控制它们的数量和大小？一个细胞如何“决定”它应该有多少个线粒体？细胞是如何构建精确排列部分的结构的，比如肌肉中的肌节，它的肌动蛋白丝排列整齐，与肌球蛋白纤维交叉在一起？细胞骨架提供了一个特别富有成效的领域，在其中开发定量模型，以解决这些形态学问题。也就是说，多年来生物学家已经获得了关于细胞骨架结构和动力学的大量定量信息。这项工作已经产生了组成细胞骨架的分子的零件清单，以及这些分子如何相互作用，而这些相互作用在细胞内如何在空间和时间上协调的问题在很大程度上仍然没有答案。PI将使用理论物理和数学来开发一种通用语言来描述细胞骨架结构的各种尺寸控制机制。亚细胞结构的组装将作为一个随机过程进行研究，该过程涉及不同的分子成分和数学上不同的反馈机制，细胞用于控制其大小。这项研究将推动统计物理学、细胞生物学和生物材料领域的发展。提出的理论研究的一个关键特征是与实验实验室密切合作，研究酵母中肌动蛋白结构的组装动力学，小鼠毛细胞中纤毛的组装，以及线虫发育胚胎中的核仁。它还将有助于培养对研究细胞生物学基本问题感兴趣的理论物理学家。

NONTECHNICAL SUMMARYThe Division of Materials Research, the Division of Molecular and Cellular Biosciences, and the Physics Division contribute funds to this award. This award supports theoretical research and education on fundamental questions of cell biology with implications for biomaterials and statistical physics. A remarkable feature of all living cells is that they contain many subcellular parts called organelles that perform different functions. Organelles come in different sizes and shapes and these physical attributes are often intimately related to their function. For example, mitochondria are compartments filled with lipid membranes folded upon themselves many times over. The large membrane supports protein machines that are imbedded in the membrane and whose function is to make cellular fuel molecules. Similarly, cells build long polymer cables of length precisely matched to the size of the cell, and are used to transport materials from one side of the cell to the other. These observations motivate the question: How do cells assemble such three-dimensional structures? While genes encoded in the cell's DNA carry the information needed to make the molecular building blocks, how they self-assemble into intricate and functional three-dimensional structures remains largely unknown. The PI will consider these fundamental questions using mathematical models for assembly of subcellular structures. These models will be tested against experimental data obtained by several collaborating biology labs. The goal will be to identify common design principles for assembly that lead to sub-cellular structures of a well-defined size and shape. New experiments in cells will be stimulated leading to potentially useful insights for making synthetic materials which self-assemble into specific shapes and sizes. The interdisciplinary nature of the research will provide opportunities for physics students to engage in cutting edge biological research. It will provide them with skills necessary to be effective members of an interdisciplinary research team consisting of biologists and physicists. These skills are particularly important for the science, technology, engineering and mathematics workforce of the future since most of the big problems facing society will require a concerted effort of scientists from different disciplines. TECHNICAL SUMMARYThe Division of Materials Research, the Division of Molecular and Cellular Biosciences, and the Physics Division contribute funds to this award. This award supports theoretical research and education on fundamental questions of cell biology with implications for biomaterials and statistical physics. Subcellular structures in cells have been observed for hundreds of years and yet it is only recently that we have developed the experimental tools to address key questions about them, such as: How do cellular organelles obtain their specific shapes? How do cells control their number and size? How does a cell 'decide' how many mitochondria should it have? How does a cell construct structures with precisely arranged parts, such as sarcomeres in muscle with its regimented arrays of actin filaments interdigitated with myosin fibers? The cytoskeleton provides a particularly fruitful arena in which to develop quantitative models that address these questions of morphology. Namely, over many years biologists have obtained a wealth of quantitative information about the structure and dynamics of the cytoskeleton. This work has produced a parts list of molecules that the cytoskeleton is made of, and how these molecules interact, while the question of how these interactions are coordinated in space and time inside the cell remains largely unanswered. The PI will use theoretical physics and mathematics to develop a common language for describing the various size control mechanisms of cytoskeleton structures. An assembly of sub-cellular structures will be investigated as a stochastic process that involves different molecular components and mathematically different feedback mechanisms that cells employ to control their size will be studied. The proposed research will advance the fields of statistical physics, cell biology, and biomaterials. One of the key features of the proposed theoretical research is a close collaboration with experimental labs that study assembly dynamics of actin structures in yeast, the assembly of cilia in mouse hair cells, and of nucleoli in developing embryos of the worm C.elegans. It will also help train theoretical physicists interested in working on fundamental problems in cell biology.