Microtubule networks and virus trafficking

微管网络和病毒贩运

基本信息

批准号：
8667733
负责人：
STEPHEN Paine GOFF
金额：
$ 179.4万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8667733
关键词：
Acetylation Actins Address Affect Antiviral Agents Architecture Binding Proteins Biological Biological Process COX7A2L Protein Cell Nucleus Cell Shape Cell surface Cells Cellular Structures Centrosome Color Crosslinker Cues DNA Viruses Development Dynein ATPase Event Filament Growth Half-Life Herpesvirus 1 Image Individual Infection Intracellular Transport Invaded Kinesin Knowledge Lead Life Link Mediating Microtubule Stabilization Microtubule-Organizing Center Microtubules Modeling Modification Molecular Motor Movement Phase Physiological Plus End of the Microtubule Post-Translational Protein Processing Principal Investigator Program Research Project Grants Proteins RNA Viruses Regulation Regulatory Pathway Retroviridae Infections Role Signal Pathway Signal Transduction Site Staging System Time Transport Vesicles Tubulin Viral Virion Virus Virus Diseases base cell motility cell type crosslink genetic regulatory protein insight macromolecule member new therapeutic target novel novel therapeutic intervention particle pathogen programs public health relevance response trafficking trans-Golgi Network viral DNA viral RNA virology

项目摘要

DESCRIPTION (provided by applicant): Upon entry into cells, many diverse viruses exploit their hosts' cytoskeletal transport networks to reach their sub-cellular site of replication, and nw viral progeny use these same networks to return to the cell surface and spread. Viruses frequently move along actin at the cell periphery before transitioning onto host microtubule (MT) networks that mediate long-range intracellular transport. MTs are highly dynamic heteropolymers of ¿/¿ tubulin (half-lives <5 min), which radiate from the perinuclear MT Organization Center (MTOC) towards the cell surface. Subsets of MTs become stabilized (half-life >1h) in response to various environmental and developmental signals, and are thought to act as specialized networks for vesicle transport during events such as cell polarization and motility. MT dynamics and stabilization are controlled by a number of highly specialized regulators, including actin-MT crosslinking factors and MT plus-end binding proteins (+TIPs), whose accumulation at MT ends is facilitated by the MT plus-end tracking protein, EB1. Movement of cargos on these MT networks involves motor proteins; generally, dynein directs minus-end and kinesins direct plus-end transport. However, our understanding of the role of MTs, their regulators and motors in the movement of viral particles during infection is severely limited. This Program Project Grant (PPG) nucleates expertise in cytoskeletal regulation, motors and MT-based motility, cell signaling and infection by diverse viruses to address these fundamental questions in mechanistic detail in a variety of systems. As a group, our interactions to date have established that both RNA and DNA viruses cause distinct MT modifications and require a range of specialized MT regulatory factors for efficient infection, including actin-MT crosslinkers, +TIPs and EB1, as well as identifying specific host motors used for virion traffickin to the nucleus. In this PPG we aim to determine the mechanistic details underlying these highly dynamic interactions between MT subsets, motors and invading virions, including the use of state-of-the-art dual-color imaging to analyze these events in real time. This integrated and interactive approach not only greatly enhances each individual project's potential by leveraging the strengths of other members, but also serves to focus our cumulative expertise on addressing key aspects of the Overall Aims of this PPG, "Microtubule Networks and Virus Trafficking". This efficient group approach has the potential to uncover fundamental new insights in MT function and regulation during viral infection that will likely be important in broaer biological contexts and may lead to the development of novel therapeutic approaches.

描述（由申请人提供）：进入细胞后，许多不同的病毒利用宿主的细胞骨架运输网络到达其亚细胞复制位点，并且病毒后代使用这些相同的网络返回细胞表面并传播病毒。在过渡到介导长程细胞内运输的宿主微管 (MT) 网络之前，它们经常沿着细胞外围的肌动蛋白移动，MT 是 ¿ 的高度动态杂聚物。 /¿微管蛋白（半衰期 <5 分钟），从核周 MT 组织中心 (MTOC) 向细胞表面辐射，MT 亚群响应各种环境和发育信号而变得稳定（半衰期 > 1 小时）。在细胞极化和运动动力学和稳定性等事件中充当囊泡运输的专门网络，由许多高度专业化的调节因子控制，包括肌动蛋白-MT 交联因子和MT 正端结合蛋白 (+TIP)，其在 MT 末端的积累由 MT 正端跟踪蛋白 EB1 促进，这些 MT 网络上的货物运动涉及运动蛋白；通常，动力蛋白引导负端，驱动蛋白引导。然而，我们对 MT、其调节器和马达在感染过程中病毒颗粒运动中的作用的了解严重有限。细胞骨架调节、运动和基于 MT 的运动、细胞信号传导和不同病毒的感染，以解决各种系统中机制细节上的这些基本问题。作为一个团队，我们迄今为止的相互作用已经确定 RNA 和 DNA 病毒都会引起不同的 MT。修饰并需要一系列专门的 MT 调节因子来实现有效感染，包括肌动蛋白-MT 交联剂、+TIP 和 EB1，以及识别用于病毒粒子运输到细胞核的特定宿主马达。确定 MT 子集、马达和入侵病毒粒子之间这些高度动态相互作用的机制细节，包括使用最先进的双色成像来实时分析这些事件，这种集成和交互的方法不仅极大地提高了这些事件的效率。通过利用其他成员的优势来增强每个项目的潜力，同时也有助于将我们积累的专业知识集中在解决该 PPG 总体目标“微管网络和病毒贩运”的关键方面。揭示病毒感染过程中 MT 功能和调节的基本新见解的潜力，这在更广泛的生物学背景中可能很重要，并可能导致新治疗方法的开发。