Origins of Cell Geometry

摘要 细胞是高度复杂的有生命的纳米机器，具有非常精确的美丽结构。 这不仅适用于纤毛虫或放射虫等自由生活的有机体，也适用于细胞 在人体内。这些复杂的结构直接与 细胞的生理功能和细胞几何形状的改变是许多 疾病状态。然而，在大多数情况下，我们几乎没有关于细胞如何 在细胞器大小和形状的水平上确定它们的几何形状。因此，理解 细胞几何学的起源仍然是细胞生物学中一个尚未解决的基本问题。 部分挑战是像元几何涉及多个空间尺度，范围从 分子长达整个细胞。跨越规模之间的差距需要我们 超越传统的分子生物学方法，引入物理学和 工程学。出于这个原因，我的建议是基于以下因素的综合组合 方法，使用几种不同的模式生物和细胞类型来解决 几个不同大小比例的单元格几何原点。在单个细胞器的水平上， 我将继续探索鞭毛长度控制的机制，作为 细胞器大小调节，重点是使用定量方法来测试一系列 细胞如何能够感知其鞭毛长度的机械模型。在… 与此同时，我们将应用我们为之制定的经验教训和方法 思考鞭毛来研究其他细胞细胞器的大小控制和几何形状， 单独的和组合的。通过同时考虑多个细胞器，我们可以 了解如何在更完整的级别上查看单元格几何图形。在更大的范围内，我们将 继续我们对经典模式生物Stentor Blue uleus的开发，作为 用于分析全球细胞形态发生和再生的基因组模型系统。 使用Stentor，我们打算探讨细胞如何知道这两个相互关联的问题 几何学已经被扰乱了，以及它是如何指导正确的细胞重新组装的 几何，这两个问题对所有细胞类型都有普遍意义，但 在斯坦托学习特别容易。我们提议的工作是统一的，重点是 一个问题-几何图形从细胞内部的哪里来。我们将使用不同的 模型系统来解决这个问题的不同方面，但在所有情况下，我们都将采取 一种结合了遗传学、基因组学、显微镜、 图像分析和数学建模。

Abstract Cells are highly complex living nanomachines with beautiful structures of great precision. This is true not only for free living organisms like ciliates or radiolarians, but also for cells inside the human body. These complicated structures are directly linked to the physiological functions of cells, and alterations in cell geometry are a hallmark of many disease states. Yet in most cases we have almost no information about how cells determine their geometry at the level of organelle size and shape. Thus, understanding the origins of cell geometry remains a fundamental unsolved problem in cell biology. Part of the challenge is that cell geometry involves multiple spatial scales ranging from molecules up to the whole cell. Spanning this gap between scales requires us to go beyond traditional molecular biology approaches and bring in methods from physics and engineering. For this reason my proposal is based on an integrated combination of approaches, using several different model organisms and cell types to address the origins of cell geometry at several different size scales. At the level of single organelles, I will continue to probe the mechanism of flagellar length control as a paradigm for organelle size regulation, with a focus on using quantitative methods to test a series of mechanistic models for how a cell might be able to sense the length of its flagellum. At the same time, we will apply the lessons and approaches that we have developed for thinking about flagella to examine size control and geometry of other cellular organelles, singly and in combination. By considering multiple organelles at the same time, we can learn how to view cell geometry at a more integrative level. At a larger scale, we will continue our development of the classic model organism, Stentor coeruleus, as a genomic model system for analyzing global cell morphogenesis and regeneration. Using Stentor, we intend to pursue the two linked questions of how a cell knows that is geometry has been perturbed, and how it directs the re-assembly of a correct cell geometry, both questions that have general significance to all cell types but which are particularly easy to study in Stentor. Our proposed work is unified by the focus on a single question – where does geometry come from inside a cell. We will use different model systems to address different aspects of this question, but in all cases we will take an interdisciplinary approach that combines tools of genetics, genomics, microscopy, image analysis, and mathematical modeling.