Actin Assembly and Cell Motility: Mechanisms and Regulation

肌动蛋白组装和细胞运动：机制和调节

• 批准号: 9252484
• 负责人: JOHN A COOPER
• 金额: $ 50.94万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252484
• 关键词: Actins; Area; Arthritis; Biological Models; Cell Shape; Cell membrane; Cells; Cytoskeleton; Disease; Electron Microscopy; Endothelial Cells; Endothelium; Environment; Faculty; Filament; Funding; Goals; Grant; Immune; Infection; Kinetics; Light; Malignant Neoplasms; Membrane; Mentors; Microfilaments; Molecular; Natural Killer Cells; Organelles; Pathologic Processes; Physiological; Physiological Processes; Plus End of the Actin Filament; Proteins; Reaction; Regulation; Research; Resolution; Scientist; Secure; Shapes; Site; System; Time; Work; Zebrafish; actin capping protein; base; cancer cell; cell motility; flexibility; insight; interest; killings; light microscopy; migration; new technology; novel; public health relevance; success

 DESCRIPTION (provided by applicant): Our lab studies molecular and cellular mechanisms for actin assembly and actin-based cell motility. We want to understand how actin filaments assemble, how they interact with other cytoskeletal components and membranes, and how these interactions dictate cell shape and movement. The MIRA goals are: 1) combining existing grants, 2) promoting flexibility in new research directions, and 3) promoting stability and mentoring. 1) Existing Grants. "Mechanisms for Transendothelial Migration" is the current title of a long-standing grant focused on actin assembly and membranes. Transendothelial migration is a new area for us, one that emerged from studies on how NK cells migrate, find and kill their target cells. We are interested in how immune and cancer cells cross the endothelium of the vasculature during physiological and pathological processes. The migrating cell and the endothelial cell both actively participate, changing shape and exerting force as a result of actin filaments interacting with the plasma membrane and intracellular membranous organelles. "Regulation of Actin Capping Protein" is the current title of a newer grant focused on novel mechanisms of regulation of actin capping protein. Capping protein is a key regulator of the availability and activity of actin- filament barbed ends. Recent discoveries of novel regulators of capping protein have revealed unexpected insights that dramatically change our view of actin assembly in cells. We now know that regulators target capping protein to sites where cells need to assemble actin filaments and that they tune its filament-capping activity to a level that is physiologically relevant for the concentrations of the reactants and kinetics of the reactions. 2) Flexibility and New Research Directions. I have been successful in pursuing new directions, using new experimental systems, and adapting to new technologies, as described in my Biosketch. New areas for our lab in this proposal include novel connections between cytoskeleton filament systems, the use of zebrafish as a vertebrate model system, light-induced control of protein activity, and super-resolution correlative light and electron microscopy. 3) Mentoring and Stability. The MIRA FAQ mentions "more time for conduct of research and mentoring junior scientists in a more stable environment," which resonates strongly with me. I enjoy serving as a mentor, and I am very proud of the success of our lab trainees and my faculty colleagues, within and outside of our department. In terms of stability, while we are grateful for our success in securing continued funding for our research, our ability to make transitions and explore new directions will be made more facile and efficient by the MIRA mechanism.

 描述（由适用提供）：我们的实验室研究肌动蛋白组装和基于肌动蛋白的细胞运动的分子和细胞机制。我们想了解肌动蛋白丝如何组装，它们如何与其他细胞骨架成分和机制相互作用，以及这些相互作用如何决定细胞的形状和运动。 MIRA目标是：1）结合现有赠款，2）促进新研究方向的灵活性，3）促进稳定和指导。 1）现有赠款。 “跨内皮迁移的机制”是一项重点是肌动蛋白组装和膜的长期赠款的标题。跨内皮迁移对我们来说是一个新领域，这是从关于NK细胞如何迁移，查找和杀死其靶细胞的研究中出现的。我们对身体和病理过程中的免疫细胞和癌细胞如何跨越脉管系统的内皮感兴趣。迁移的细胞和内皮细胞都积极参与，由于肌动蛋白丝与质膜和细胞内膜细胞器相互作用而改变形状和发挥作用。 “肌动蛋白上限蛋白的调节”是较新的赠款的当前标题，该授予重点是肌动蛋白上限蛋白调节的新机制。封盖蛋白是肌动蛋白细丝末端的可用性和活性的关键调节剂。最新发现的新型调节器 封盖蛋白已经揭示了意外的见解，这些见解极大地改变了我们对细胞中肌动蛋白组装的看法。我们现在知道，调节剂将蛋白质靶向细胞需要组装肌动蛋白丝的位点，并且它们将其丝贴活性调节至与反应物的浓度和反应动力学的物理相关的水平。 2） 灵活性和新研究方向。如我的BioSketch所述，我已经成功地使用了新的方向，使用新的实验系统并适应了新技术。该提案中的实验室的新领域包括细胞骨架细丝系统之间的新连接，斑马鱼用作脊椎动物模型系统，光诱导的蛋白质活性的控制以及超分辨率的相关光和电子显微镜。 3）指导和稳定。 Mira FAQ提到“在更稳定的环境下进行研究和心理初级科学家的更多时间”，这引起了我的共鸣。我喜欢一种心态，我为我们部门内外的实验室学员和我的教职员工的成功感到自豪。在稳定性方面，尽管我们成功地为我们的研究获得了持续资金，但我们有能力进行过渡和探索新方向的能力将通过MIRA机制更加便捷和高效。