ACTIN ASSEMBLY AND CELL MOTILITY: MECHANISMS AND REGULATION

肌动蛋白组装和细胞运动：机制和调节

基本信息

批准号：
10075071
负责人：
JOHN A COOPER
金额：
$ 17.16万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

Research Plan Summary / Abstract from Parent Grant (R35 GM118171) 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. 1

研究计划家长补助金摘要/摘要 (R35 GM118171) 我们的实验室研究肌动蛋白组装和基于肌动蛋白的细胞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相互作用。成分和膜，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) 合并现有资助，2) 促进新研究的灵活性方向，以及 3) 促进稳定性和指导。 1）现有赠款“跨内皮迁移机制”是一项长期资助的当前标题。长期拨款重点关注肌动蛋白组装和膜迁移是一个新领域。我们是通过研究 NK 细胞如何迁移、发现并杀死其靶细胞而诞生的。对免疫细胞和癌细胞在生理过程中如何穿过脉管系统内皮感兴趣迁移细胞和内皮细胞都积极参与、改变。由于肌动蛋白丝与质膜相互作用而形成形状并施加力，细胞内的膜细胞器。 “肌动蛋白封盖蛋白的调节”是一项专注于新颖的新资助的当前标题肌动蛋白加帽蛋白的调节机制加帽蛋白是可用性的关键调节剂。和肌动蛋白丝带刺末端的活性最近发现了加帽蛋白的新型调节剂。揭示了意想不到的见解，极大地改变了我们对细胞中肌动蛋白组装的看法。调节器将加帽蛋白靶向细胞需要组装肌动蛋白丝的位点，并且它们将其丝状帽活性调节至与生理学浓度相关的水平反应物和反应动力学。 2）灵活性和新的研究方向我成功地追求了新的方向。使用新的实验系统并适应新技术，如我的 Biosketch New 中所述。我们实验室在该提案中的领域包括细胞骨架丝系统之间的新颖连接，使用斑马鱼作为脊椎动物模型系统，光诱导控制蛋白质活性，以及超级分辨率相关光学和电子显微镜。 3) 指导和稳定性。MIRA 常见问题解答提到“有更多时间进行研究和维护”。在更稳定的环境中指导年轻科学家”，这引起了我的强烈共鸣。作为导师，我为我们的实验室实习生和我的教职同事的成功感到非常自豪，在我们部门内部和外部的稳定性方面，我们对我们在方面的成功表示感谢。确保我们的研究持续得到资助，确保我们有能力进行转型和探索新方向 MIRA机制将让一切变得更加便捷和高效。 1