Microbial mobilization of the actin cytoskeleton

肌动蛋白细胞骨架的微生物动员

• 批准号: 9912779
• 负责人: Matthew D Welch
• 金额: $ 38.52万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912779
• 关键词: Actins; Address; Animals; Baculoviruses; Behavior; Biochemical; Biological; Burkholderia; Cardiovascular Diseases; Cell Communication; Cell Cycle Regulation; Cell Death; Cell Nucleus; Cell fusion; Cell membrane; Cell physiology; Cells; Cellular biology; Cytoplasm; Cytoskeleton; Development; Diagnosis; Disease; Event; Functional disorder; Gene Expression; Infection; Inflammation; Inflammatory; Intracellular Transport; Knowledge; Lead; Malignant Neoplasms; Mammalian Genetics; Membrane; Methods; Microbe; Microbial Genetics; Microbiology; Modeling; Movement; Mycobacterium marinum; Neoplasm Metastasis; Nuclear; Nuclear Envelope; Nucleopolyhedrovirus; Pathogenesis; Play; Polymers; Positioning Attribute; Property; Proteins; Recycling; Regulation; Research; Role; Shapes; System; Work; biophysical techniques; cell behavior; host colonization; human disease; imaging approach; insight; instrument; microbial; migration; novel strategies; polymerization; prevent; tool; trafficking

PROJECT SUMMARY/ABSTRACT The actin cytoskeleton is crucial for cellular properties and behaviors including shape, migration, and division, as well as for cell-cell connections and fusion during animal development. Because of these numerous essential functions in cell physiology, actin dysfunction is also a common contributor to pathogenesis, for example in inflammation, cardiovascular disease, cancer metastasis, and microbial infection. Despite many years of study, however, understanding how actin assembly is regulated and harnessed in the cytoplasm and nucleus for intracellular events, cellular behaviors, and cell-cell interactions remains a key outstanding problem in cell biology. My lab has taken a distinctive approach to address this important gap in knowledge, which is to examine the interactions between infectious microbes and the actin cytoskeleton as a window into actin regulation and function. Our approach leverages the fact that many infectious microbes colonize host cells through their ability to target actin, and builds on numerous examples of how studying the interactions between microbes and host cells has enhanced our understanding of cytoskeleton dynamics, as well as membrane trafficking, cell cycle regulation, protein recycling, and cell death. The research described in this MIRA application makes use of microbes as tools to address three fundamental cell biological questions: (1) How is actin polymerization at membranes regulated and mobilized to drive movement? (2) How and why is actin transported into and polymerized within the nucleus for gene expression, nuclear organization, intranuclear movement, and nuclear envelope dynamics? (3) How is actin polymerization in plasma membrane protrusions harnessed to induce cell-cell fusion? We will investigate these questions using three model microbes, each of which mobilizes actin in a manner that makes it a unique and powerful instrument: Mycobacterium marinum as a tool to understand the regulation of actin assembly at membranes to drive intracellular movement; the baculovirus Autographa californica multiple nucleopolyhedrovirus as a tool to understand the regulation and function of actin in the nucleus; and Burkholderia thailandensis as a tool to understand the role of actin in cell-cell fusion. By leveraging our expertise in both microbiology and cell biology, deploying a synergistic combination of microbial and mammalian genetic methods, and employing biochemical, biophysical and imaging approaches, we are uniquely positioned to advance the field forward. Our results will enhance our understanding of the mechanisms of actin regulation and may provide new insights into diagnosing, treating, and preventing diseases associated with actin dysfunction including inflammatory and cardiovascular diseases, cancer, and microbial infection.

项目摘要/摘要 肌动蛋白细胞骨架对于包括形状，迁移和分裂在内的细胞特性和行为至关重要， 以及动物发育过程中的细胞 - 细胞连接和融合。因为这些 细胞生理学的基本功能，肌动蛋白功能障碍也是发病机理的常见因素，因为 炎症，心血管疾病，癌症转移和微生物感染的示例。尽管有很多 但是，多年的研究了解如何在细胞质中调节和利用肌动蛋白组装 细胞内事件，细胞行为和细胞 - 细胞相互作用的核仍然是关键的关键问题 在细胞生物学中。我的实验室采取了一种独特的方法来解决知识中的这一重要差距，即 检查传染性微生物与肌动蛋白细胞骨架之间的相互作用作为肌动蛋白的窗口 调节和功能。我们的方法利用了许多传染性微生物定居宿主细胞的事实 通过它们靶向肌动蛋白的能力，并基于许多示例，说明如何研究 微生物和宿主细胞增强了我们对细胞骨架动力学以及膜的理解 运输，细胞周期调节，蛋白质回收和细胞死亡。 此MIRA应用中描述的研究利用微生物作为解决三个基本的工具 细胞生物学问题：（1）如何调节膜的肌动蛋白聚合是如何调节和动员以驱动的 移动？ （2）肌动蛋白如何以及为什么将肌动蛋白转移到细胞核中，以进行基因表达，以用于基因表达， 核组织，核内运动和核包膜动态？ （3）肌动蛋白聚合如何 在质膜突起中，要诱导细胞 - 细胞融合？我们将调查这些问题 使用三个模型微生物，每种微生物以使其成为独特而强大的方式动员肌动蛋白 仪器：分枝杆菌海洋作为了解在膜上肌动蛋白组件调节的工具 驱动细胞内运动； Baculovirus Autographa califorchica多重多核菌病毒作为一种工具 了解肌动蛋白在细胞核中的调节和功能；和Burkholderia Thailandensis作为一种工具 了解肌动蛋白在细胞细胞融合中的作用。通过利用我们在微生物学和细胞生物学方面的专业知识， 部署微生物和哺乳动物遗传方法的协同组合，并采用生化， 生物物理和成像方法，我们是独特的定位，可以向前推进该领域。我们的结果将会 增强我们对肌动蛋白调节机制的理解，并可能为 诊断，治疗和预防与肌动蛋白功能障碍有关的疾病，包括炎症和 心血管疾病，癌症和微生物感染。