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.

概括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，但许多分化细胞都具有中心体微管阵列。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，通常贯穿生物体的整个生命周期。我的实验室研究的图案心体微管及其对秀丽隐杆线虫货物运输的影响。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并且兼容的算法货物运输的实时成像。我们进行了公正的筛选以发现新型微管调节因子并正在使用遗传学、成像和生化方法来了解其机制。与此同时，我们通过检查微管阵列模式的影响来研究微管阵列模式的生物学意义长程细胞内运输的调节剂。该提案详细说明了我们实验的建立系统、屏幕的设计和实现以及所选调节器的初步表征。那么它概述了我们未来五年的主要目标：完成筛选并阐明其机制建立中心体阵列架构。这些研究将确定稳态阵列架构如何来自对单一聚合物成核和动力学的控制以及它如何适应的功能特化细胞。微管支持细胞迁移、极化等基本生物过程和货物运输。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中心体阵列的构建模块，它将决定它们图案化的机制细胞骨架并调节运输。许多疾病涉及细胞骨架缺陷表明从长远来看，我们的研究将有助于阐明发生细胞功能障碍的机制患病期间。