Dynamic architecture and function of microtubule networks

微管网络的动态结构和功能

• 批准号: 10623051
• 负责人: Irina Kaverina
• 金额: $ 43.59万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623051
• 关键词: Actins; Address; Affect; Affinity; Architecture; Automobile Driving; Behavior; Biochemistry; Biological; Biopolymers; Cell Cycle; Cell Cycle Stage; Cell physiology; Cells; Cellular Structures; Cellular biology; Collaborations; Complex; Computer Models; Cytoskeleton; Event; Funding; Funding Mechanisms; Geometry; Goals; Golgi Apparatus; Individual; Interphase; Intracellular Space; Intracellular Transport; Laboratories; Laboratory Study; MAPT gene; Metabolic; Methods; Microtubule-Associated Proteins; Microtubule-Organizing Center; Microtubules; Molecular; Molecular Motors; National Institute of General Medical Sciences; Physiological; Positioning Attribute; Process; Publishing; Regulation; Research; Resources; Role; Scaffolding Protein; Signal Transduction; Site; Structure; System; Time; Translating; Tumor Suppressor Proteins; crosslink; human disease; insight; novel; programs; response; trafficking

Summary Microtubules (MTs) are dynamic biopolymers, which serve as major highways for intracellular transport. MT networks are critical for cell physiology, and their disturbance underlies many human diseases. My laboratory studies global mechanisms allowing MTs to perfectly attribute to specific cellular functions. MT-dependent transport arranges multiple cell components at the same time. To address these complex requirements, MT geometry, molecular motor affinity, and/or MT association with to other cell components are tightly regulated. MT network geometry changes depending on the sites of new MT outgrowth (the MT-organizing centers, or MTOCs), local stabilization/disassembly of MTs, and MT anchoring to other structures. Furthermore, the affinity of individual MTs to molecular motors can be modulated to affect intracellular transport. Finally, MTs can scaffold proteins or be cross-linked with other cytoskeletal components. All those mechanisms that tailor MT organization to distinct cell functions can respond dynamically to cell-signaling inputs and the physiological context. Together, molecular regulation and functional specialization of MT networks comprise a global field in basic cell biology with numerous unanswered questions. My research program’s long-term goals include defining: how interphase MT networks are built and regulated; specific mechanisms tailoring MT biochemistry and geometry to specific cellular needs; the methods whereby MTs collaborate with other cellular systems to build intracellular space; and, how MTs switch their functional loads between distinct tasks to arrange integral cell architecture under changing signaling conditions. Since April 2018, the NIGMS MIRA funding mechanism has been an invaluable resource allowing us to explore these basic, fundamental biological problems. We have published several central advances toward our global and interactive goals. Among other findings, we brought a new mechanistic understanding of Golgi-derived MT networks (GDMTs, which were identified in our prior studies); described novel, surprising functions for MT- associated proteins (MAPs) tau, CLASP2, and CAMSAP2; utilized collaborations with experts in computational modeling for deep understanding of MT functions in secretory trafficking and actin cytoskeleton dynamics; and, discovered a previously overlooked, physiologically important Golgi complex behavior in the cell cycle. In the next five years, I will extend mechanistic and functional insights in two broad directions of my program’s extant NIGMS-funded research. (I) We will determine how the versatility of MT functions is tuned by multifunctional MAPs, focusing on (a) secretory trafficking through the Golgi axis and (b) the organization of the actin cytoskeleton. Initial studies will evaluate the roles of MT regulators CLASPs and a MT-stabilizing tumor suppressor RASSF1A. (II) We will expand our studies of MT-dependent Golgi positioning to dissect (a) molecular mechanisms driving this process and (b) the significance of Golgi relocation in distinct cell cycle stages.

总结 微管（MT）是动态的生物聚合物，作为细胞内运输的主要通道。Mt 网络对于细胞生理学至关重要，它们的干扰是许多人类疾病的基础。我的实验室 研究使MT完美地归属于特定细胞功能的全局机制。 MT依赖性运输同时排列多个细胞组分。为了解决这些复杂的 在一些实施方案中，MT的结构、要求、MT几何结构、分子马达亲和力和/或MT与其它细胞组分的缔合是 严格监管。MT网络几何形状的变化取决于新的MT产物（MT组织）的位置。 中心或MTOCs）、MT的局部稳定/拆卸以及MT锚定到其他结构。此外，委员会认为， 可以调节单个MT对分子马达的亲和力以影响细胞内转运。最后，MT 可以为蛋白质提供支架或与其他细胞骨架成分交联。所有这些机制， 不同细胞功能的组织可以动态地响应细胞信号输入和生理信号。 上下文MT网络的分子调节和功能专业化共同构成了一个全球领域， 基础细胞生物学还有很多未解之谜我的研究计划的长期目标包括 定义：间期MT网络是如何建立和调节的;定制MT的具体机制 生物化学和几何形状的特定细胞的需要; MT与其他合作的方法 细胞系统建立细胞内空间;以及，MT如何在不同的细胞之间切换其功能负荷。 任务来在变化的信令条件下安排完整的小区架构。 自2018年4月以来，NIGMS MIRA资助机制一直是一个宝贵的资源，使我们能够探索 这些基本的生物学问题。我们已经发表了几项核心进展， 互动的目标。在其他发现中，我们对高尔基体衍生的MT有了新的机制理解， 网络（GDMT，这是在我们以前的研究中确定）;描述了新的，令人惊讶的功能MT- 相关蛋白（MAPs）tau、CLASP 2和CAMSAP 2;利用与计算领域专家的合作， 为深入理解MT在分泌运输和肌动蛋白细胞骨架动力学中的功能而建模;以及， 发现了一个以前被忽视的，在生理上重要的高尔基复合体在细胞周期中的行为。 在接下来的五年里，我将在我的计划的两个广泛的方向扩展机械和功能的见解， NIGMS资助的研究。(I)我们将通过以下方式确定如何调整MT函数的多功能性： 多功能的地图，重点是（a）分泌贩运通过高尔基体轴和（B）的组织， 肌动蛋白细胞骨架初步研究将评估MT调节剂CLASP和MT稳定肿瘤的作用， 抑制基因RASSF 1A。(II)我们将扩大我们的研究MT依赖的高尔基体定位解剖（a）分子 驱动该过程的机制和（B）高尔基体重新定位在不同细胞周期阶段中的意义。