Mechanisms for building and remodeling microtubule arrays

构建和重塑微管阵列的机制

• 批准号: 10531239
• 负责人: RAMANAND DIXIT
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10531239
• 关键词: Address; Animals; Cells; Cellular biology; Complex; Cytoskeleton; Defect; Development; Disease; Eukaryotic Cell; Evolution; Filament; Goals; Growth; Health; Human; Link; Maintenance; Malignant Neoplasms; Microfluidic Microchips; Microtubule Stabilization; Microtubules; Minus End of the Microtubule; Molecular; Mouse-ear Cress; Neurodegenerative Disorders; Organism; Pattern; Physiology; Plants; Plus End of the Microtubule; Polymers; Proteins; Reagent; Research; Rest; Shapes; Signal Transduction; Structure; System; Time; developmental disease; genetic regulatory protein; improved; insight; interdisciplinary approach; internal control; katanin; migration; programs; protein crosslink; response; scaffold; tool

Project Summary Control of the internal organization of cells is essential to the form and function of all organisms. This ability rests largely on an intricate protein filament network called the cytoskeleton which serves as a scaffolding structure to pattern cellular contents in space and time. Unlike human-made scaffolding structures, the cytoskeleton is highly dynamic and is able to change its configuration in response to developmental and environmental signals, allowing cells to adapt to changing conditions. Thus, the cytoskeleton is like an ever- changing structural “diagram”, and the goal of my research program is to understand how these diagrams are generated to execute essential cellular activities that underlie growth, development and physiology. Our research focuses on mechanisms for the creation, maintenance and restructuring of the microtubule cytoskeleton using the cortical microtubule array of Arabidopsis thaliana as an experimentally tractable system. We use a multidisciplinary approach and benefit from an extensive network of close collaborators with whom we freely share reagents and ideas. These advantages have allowed us to address previously intractable questions about cytoskeleton structure and function. Here, we will build on our recent progress to focus on four major goals: Goal 1) characterize new regulatory mechanisms that specifically tune the microtubule severing activity of katanin to uncover how various internal and external signals influence the assembly and disassembly of diverse microtubule structures through katanin. Goal 2) elucidate the structural dynamics that determine the functional diversity of MAP65 microtubule crosslinking proteins to gain insight into how evolution selected particular MAP65 sequences for specialized functions and to enable the creation of new tools to manipulate microtubule function in plants and animals. Goal 3) uncover the structure and mechanism of action of a new class of microtubule minus-end regulators to understand how TOG domains, which are typically associated with microtubule plus-end tracking proteins, have been repurposed to recognize and stabilize microtubule minus-ends. Goal 4) develop a new microfluidics chip platform to analyze the complex relationships between sets of microtubule regulatory proteins to obtain a clear and integrated picture of how concurrent molecular activities dynamically pattern microtubule structures. Together, these synergistic projects will provide a mechanistically detailed picture of the inner workings of complex microtubule structures and advance our understanding of their functions in cell biology and disease.

项目摘要 细胞内部组织的控制对于所有生物体的形式和功能都是必不可少的。这种能力 很大程度上依赖于一种称为细胞骨架的复杂蛋白质细丝网络， 在空间和时间上对细胞内容进行模式化。与人造脚手架结构不同， 细胞骨架是高度动态的，并且能够响应发育和生长而改变其构型。 环境信号，使细胞能够适应不断变化的条件。因此，细胞骨架就像是一个永远- 我的研究计划的目标是了解这些图表是如何变化的， 产生执行基本的细胞活动的基础生长，发育和生理。 我们的研究重点是创造，维护和重组的机制， 微管细胞骨架使用拟南芥皮层微管阵列作为实验 易处理的系统我们采用多学科的方法，并受益于广泛的密切合作网络。 与我们自由分享试剂和想法的合作者。这些优势使我们能够解决 以前难以解决的关于细胞骨架结构和功能的问题在这里，我们将建立在我们最近的 目标1）描述新的监管机制， 微管切断活动katanin揭示如何各种内部和外部信号影响 通过katanin组装和拆卸不同的微管结构。目标2：阐明结构 动力学，确定MAP 65微管交联蛋白的功能多样性，以深入了解 进化是如何选择特定的MAP 65序列来实现专门的功能， 操纵植物和动物微管功能的新工具。目标3：揭示结构， 一类新的微管负末端调节剂的作用机制，以了解TOG结构域， 通常与微管加末端跟踪蛋白相关， 并稳定微管负端。目标4）开发一种新的微流控芯片平台， 微管调节蛋白之间的复杂关系，以获得清晰和完整的图像 同时发生的分子活动如何动态地塑造微管结构。总之，这些协同 项目将提供复杂微管结构内部运作的详细机械图 并促进我们对它们在细胞生物学和疾病中的功能的理解。