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Patterning acentrosomal microtubule arrays

中心体微管阵列图案化

基本信息

批准号：
10797074
负责人：
Shaul Yogev
金额：
$ 13.49万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

Summary 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.

摘要微管细胞骨架支持细胞分裂、细胞形态和细胞内货物运输。虽然中心体是分裂细胞中微管成核的主要部位，但许多分化的细胞无着丝体微管阵列。突出的例子包括生殖系细胞、植物表皮、上皮和神经元。要了解细胞分化，关键是要了解无着丝体阵列结构是如何设置的。以实现聚合物数量、长度和动态的特定模式，以支持专门的细胞功能，通常贯穿有机体的整个生命。我的实验室研究的是线虫无着丝体微管及其对货物运输的影响。我们开发了成像工具和允许对体内微管组织进行前所未有的分析的算法，并且是兼容的货物运输的实况成像。我们进行了无偏筛选以发现新的微管调节因子并正在使用遗传学、成像和生化方法来了解它们的机制。同时，我们正在通过检测微管阵列模式的影响来研究其生物学意义监管机构对远距离细胞内运输的监管。这项建议详细说明了建立我们的试验性系统的设计与实现，并初步表征了调整器的选择。然后它概述了我们未来五年的主要目标：完成筛选并阐明建立非均匀体阵列体系结构。这些研究将确定稳态阵列体系结构如何从单一聚合物成核和动力学的控制中出现，以及它如何适应特化细胞。微管支持基本的生物过程，如细胞迁移、极化和货物运输。因此，我们的工作将产生重大影响：它将确定安排无着丝体排列的构建块，它将决定它们形成模式的机制细胞骨架和调节运输。细胞骨架缺陷与多种疾病的关系表明从长远来看，我们的研究将有助于阐明细胞功能障碍的发生机制。在疾病期间。