Microbial mobilization of the actin cytoskeleton

肌动蛋白细胞骨架的微生物动员

基本信息

批准号：
10623626
负责人：
Matthew D Welch
金额：
$ 47.67万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10623626
关键词：
Actins Address Baculoviruses Behavior Biochemical Biological Biological Process Burkholderia Cardiovascular Diseases Cell Communication Cell Nucleus Cell fusion Cell membrane Cell physiology Cells Cellular biology Cytoplasm Cytoskeleton Diagnosis Disease Event Extracellular Matrix Functional disorder Funding Gene Expression Genetic Human Infection Inflammation Intracellular Transport Knowledge Membrane Methods Microbe Microbiology Modeling Molecular Movement Mycobacterium marinum National Institute of General Medical Sciences Neoplasm Metastasis Nuclear Nuclear Envelope Nucleopolyhedrovirus Pathogenesis Play Polymers Positioning Attribute Property Regulation Research Role Shapes Work cell behavior host colonization host-microbe interactions human disease imaging approach insight microbial migration novel strategies polymerization prevent response tool

项目摘要

PROJECT SUMMARY/ABSTRACT The actin cytoskeleton is crucial for cellular properties and behaviors including shape, migration, and division. It is also critical for cell-cell and cell-extracellular matrix connections as well as cell-cell fusion. 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. In our NIGMS-funded research, my lab has taken a distinctive approach to address this important gap in knowledge, which is to examine the interactions between microbes that do not cause serious human illness and the host cell actin cytoskeleton as a window into actin regulation and function. Our approach leverages the fact that microbes colonize host cells through their ability to target actin, often eliciting amplified cellular responses by mimicking or manipulating host molecules, making them powerful tools for revealing molecular mechanisms of actin regulation and function. This scientific premise is supported by many examples of how studying microbe-host interactions has enhanced our understanding of basic cell biological processes. 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 that infect cells and mobilize actin in a manner that makes them powerful cell biological tools: 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 cell biology and microbiology, and deploying a synergistic combination of microbial and host genetic methods, advanced imaging approaches, and biochemical methods, we are uniquely positioned to advance the field. 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.

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。它对于细胞 - 细胞和细胞 - 细胞基质基质连接以及细胞 - 细胞融合也至关重要。因为这些肌动蛋白功能障碍在细胞生理学中的许多基本功能也是发病机理的常见因素，例如，在炎症，心血管疾病，癌症转移和微生物感染中。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。在我们的NIGMS资助的研究中，我的实验室采取了一种独特的方法来解决这一重要的知识差距，即检查不会引起严重人类的微生物之间的相互作用疾病和宿主细胞肌动蛋白细胞骨架作为肌动蛋白调节和功能的窗口。我们的方法利用微生物通过靶向肌动蛋白的能力定居的事实，通常会引起放大通过模仿或操纵宿主分子来产生蜂窝响应，使其成为揭示的强大工具肌动蛋白调节和功能的分子机制。这个科学前提得到了许多例子的支持研究微生物 - 宿主相互作用如何增强了我们对基本细胞生物过程的理解。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？我们将使用三种模型的微生物，可感染细胞和动员肌动蛋白，以使它们具有强大的细胞生物学工具：分枝杆菌码头作为了解肌动蛋白组件在膜上驱动的工具细胞内运动； 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。通过利用我们在细胞生物学和微生物学方面的专业知识，并部署微生物和宿主遗传方法的协同组合，高级成像方法，和生化方法，我们是独特的位置，可以推进该领域。我们的结果将增强我们的了解肌动蛋白调节的机制，并可能为诊断，治疗和预防与肌动蛋白功能障碍相关的疾病。