Origins of Cell Geometry

细胞几何的起源

• 批准号: 10565687
• 负责人: Wallace Marshall
• 金额: $ 64.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10565687
• 关键词: Abnormal Cell; Address; Biological Models; Cell physiology; Cells; Cellular Structures; Cellular biology; Complex; Development; Diagnosis; Disease; Engineering; Flagella; Genetic; Genomics; Geometry; Human body; Image Analysis; Learning; Length; Life; Link; Methods; Microscope; Microscopy; Modeling; Molecular Biology; Morphogenesis; Natural regeneration; Organelles; Organism; Physics; Physiological; Regulation; Series; Shapes; Structure; Testing; Thinking; Time; Work; cancer type; cell type; interdisciplinary approach; mathematical model; model organism; nanomachine; tool

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.

摘要 细胞是高度复杂的活纳米机器，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物， 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细胞的标志。 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决定它们的几何形状。因此，理解 细胞几何形状的起源仍然是细胞生物学中未解决的基本问题。 挑战的一部分是细胞几何学涉及多个空间尺度， 分子到整个细胞。跨越尺度之间的差距需要我们去 超越传统的分子生物学方法，引入物理学方法， 工程.因此，我的建议是基于以下方面的综合结合： 方法，使用几种不同的模式生物和细胞类型来解决 细胞几何形状的起源在几个不同的大小尺度。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，作为一个范例， 细胞器大小调节，重点是使用定量方法来测试一系列 细胞如何感知鞭毛长度的机制模型。在 与此同时，我们将应用我们为实现这一目标而制定的经验教训和方法， 思考鞭毛来研究其他细胞器的大小控制和几何形状， 单独地和组合地。通过同时考虑多个细胞器，我们可以 了解如何在更全面级别查看单元格几何形状。在更大的范围内，我们将 继续我们的发展的经典模式生物，Stentor蓝斑，作为一个 用于分析整体细胞形态发生和再生的基因组模型系统。 使用Stentor，我们打算追求两个相关的问题，即细胞如何知道它是 几何结构被扰动，以及它如何指导正确细胞的重新组装， 几何学，这两个问题对所有细胞类型都具有普遍意义，但 特别容易在Stentor学习。我们建议的工作是统一的重点， 只有一个问题--细胞内部的几何结构是从哪里来的。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，我们将采取 一种跨学科的方法，结合了遗传学，基因组学，显微镜， 图像分析和数学建模。