Patterning acentrosomal microtubule arrays

中心体微管阵列图案化

• 批准号: 10456992
• 负责人: Shaul Yogev
• 金额: $ 41.87万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-12 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456992
• 关键词: Algorithms; Architecture; Biochemical; Biological; Biological Process; Caenorhabditis elegans; Cell Differentiation process; Cell division; Cell physiology; Cells; Cellular Morphology; Centrosome; Cytoskeleton; Defect; Disease; Epithelial; Functional disorder; Genetic; Goals; Health; Human; Image; Imaging Device; Intracellular Transport; Knowledge; Laboratory Study; Learning; Length; Life; Light; Methods; Microtubules; Neurons; Organism; Pattern; Plant Epidermis; Polymers; Role; Site; Supporting Cell; System; Work; cell motility; design; improved; in vivo; novel

Abstract The microtubule cytoskeleton supports cell-division, cellular morphology and intracellular cargo transport. While the centrosome is a major site of microtubule nucleation in dividing cells, many differentiated cells harbor acentrosomal microtubule arrays. Prominent examples include germline cells, plant epidermis, epithelia and neurons. To understand cellular differentiation, it is crucial to learn how acentrosomal array architecture is set up to achieve a specific pattern of polymer numbers, length and dynamics that would support specialized cellular functions, often throughout the life of an organism. My laboratory studies the patterning of acentrosomal microtubules and its effect on cargo transport in C. elegans. We developed imaging tools and algorithms that allow an unprecedented level of analysis of microtubule organization in vivo and are compatible with live-imaging of cargo transport. We conducted unbiased screens to uncover novel microtubule regulators and are using genetics, imaging, and biochemical methods to understand their mechanisms. In parallel, we are investigating the biological significance of microtubule array patterns by examining the effects of these regulators on long-range intracellular transport. This proposal details the establishment of our experimental system, design and implementation of the screen, and preliminary characterization of select regulators. It then outlines our main goals for the next five years: completing the screen and elucidating the mechanisms that establish acentrosomal array architecture. These studies will determine how steady-state array architecture emerges from the control of single polymer nucleation and dynamics and how it is adapted to the function of specialized cells. Microtubules support fundamental biological processes such as cell migration, polarization and cargo transport. Hence, our work will have a significant impact: It will identify novel regulators that arrange the building blocks of acentrosomal arrays and it will determine the mechanisms by which they pattern the cytoskeleton and regulate transport. The involvement of cytoskeletal defects in numerous disorders suggests that in the long-range, our studies will help to shed light on mechanisms of cellular dysfunction that occurs during disease.

抽象的 微管细胞骨架支持细胞分裂、细胞形态和细胞内货物运输。尽管 中心体是分裂细胞中微管成核的主要部位，许多分化细胞都具有中心体 中心体微管阵列。突出的例子包括生殖细胞、植物表皮、上皮细胞和 神经元。要了解细胞分化，了解中心体阵列架构的设置至关重要 达到特定的聚合物数量、长度和动力学模式，以支持专门的细胞 功能，通常贯穿有机体的整个生命周期。 我的实验室研究秀丽隐杆线虫的中心体微管的模式及其对货物运输的影响。 我们开发了成像工具和算法，可以对微管进行前所未有的分析 体内组织并与货物运输的实时成像兼容。我们进行了公正的筛选 发现新的微管调节因子，并使用遗传学、成像和生化方法来理解 他们的机制。与此同时，我们正在研究微管阵列模式的生物学意义 检查这些调节剂对长程细胞内运输的影响。该提案详细说明了 实验系统的建立，屏幕的设计与实现，以及初步的 选定调节器的特性。然后概述了我们未来五年的主要目标：完成屏幕 并阐明建立中心体阵列架构的机制。这些研究将决定 稳态阵列结构如何从单一聚合物成核和动力学的控制中出现 它如何适应特化细胞的功能。 微管支持细胞迁移、极化和货物运输等基本生物过程。 因此，我们的工作将产生重大影响：它将确定新的监管机构来安排构建模块 中心体阵列，它将确定它们塑造细胞骨架并调节的机制 运输。许多疾病中细胞骨架缺陷的参与表明，从长远来看，我们的 研究将有助于阐明疾病期间发生的细胞功能障碍的机制。