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: 9457467
• 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/9457467
• 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; 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（由申请人提供）：我们的实验室研究肌动蛋白组装和肌动蛋白为基础的细胞运动的分子和细胞机制。我们希望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膜相互作用，以及这些相互作用如何决定细胞的形状和运动。 MIRA的目标是：1）结合现有的赠款，2）促进新的研究方向的灵活性，以及3）促进稳定和指导。 1)现有赠款。“跨内皮迁移机制”是一项长期资助的当前标题，该资助专注于肌动蛋白组装和膜。跨内皮细胞迁移对我们来说是一个新的领域，它是从NK细胞如何迁移、找到并杀死其靶细胞的研究中出现的。我们感兴趣的是在生理和病理过程中免疫细胞和癌细胞如何穿过血管内皮。迁移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并施加力。 “肌动蛋白帽蛋白的调节”是一个新的授权集中在肌动蛋白帽蛋白调节的新机制的当前标题。加帽蛋白是肌动蛋白丝倒刺末端可用性和活性的关键调节因子。新的调节剂的最新发现 帽蛋白揭示了意想不到的见解，大大改变了我们对细胞中肌动蛋白组装的看法。我们现在知道，调节因子将加帽蛋白定位到细胞需要组装肌动蛋白丝的位置，并将其加帽活性调节到与反应物浓度和反应动力学生理相关的水平。 （二） 灵活性和新的研究方向我已经成功地追求新的方向，使用新的实验系统，并适应新的技术，如我的Biosketch所述。我们实验室在这项提案中的新领域包括细胞骨架细丝系统之间的新连接，斑马鱼作为脊椎动物模型系统的使用，蛋白质活性的光诱导控制，以及超分辨率相关光学和电子显微镜。 3)指导和稳定性。MIRA常见问题解答中提到“在更稳定的环境中有更多的时间进行研究和指导初级科学家”，这引起了我的强烈共鸣。我喜欢担任导师，我为我们的实验室学员和我的系内外同事的成功感到自豪。在稳定性方面，虽然我们感谢我们成功地为我们的研究获得持续的资金，但我们进行过渡和探索新方向的能力将通过MIRA机制变得更加容易和有效。