CAREER: Computational and Theoretical Investigation of Actomyosin Contraction Systems

职业：肌动球蛋白收缩系统的计算和理论研究

• 批准号: 2340865
• 负责人: Julio Belmonte
• 金额: $ 53.69万
• 依托单位: North Carolina State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-04-01 至 2029-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2340865&HistoricalAwards=false
• 关键词: CAREER; Computational; Theoretical; Investigation; Actomyosin

The function and development of organisms depends on the incessant activities of its cells. As we growth from a small embryo, cells are constantly growing, dividing, migrating, changing shapes and pulling on each other. Even as adults, our cells continue these processes to maintain body functions and heal in response to injury. All these activities rely on the cells’ ability to generate and transmit forces. The actin cytoskeleton, a meshwork of small, dynamic filaments (actin) and molecular motors that exists inside each cell, is the main driver of force generation and propagation within cells and across tissues and organs.All cells need a functional actin cytoskeleton to maintain their shapes, divide into new cells and drive morphogenesis during development. Without an optimally functioning actin cytoskeleton, cells’ ability to migrate, differentiate, divide and respond to injury is compromised, leading to birth defects, cancers, fibrosis, immunodeficiencies, etc. To fully understand these processes, we need to first understand how the actin cytoskeleton works as a function of its components (motors, filaments and crosslinkers), and how it generates and transmits forces within and between cells. Elucidation of the actin cytoskeleton’s activities from a molecular (bottom up) view, is imperative in order to provide a mechanistic understanding of all its associated cell processes and provide new therapeutic targets related to cytoskeletal dysfunction.Experimental cell biology and in vitro studies have revealed many aspects of actin cytoskeleton contraction, such as the movement of molecular motors, the actin and motor organization underneath cell membranes (the cortex), and their role during cell division. However, many important questions that must be addressed are extremely difficult, if not impossible, to probe with experiments alone. These include: 1) What are the multiple mechanisms that the actin cytoskeleton use to contract?; 2) What makes one contraction mechanism dominant over the others?; 3) How much force can a network produce?; and 4) How do adjacent networks interact?Fortunately, there have been dramatic recent improvements in computer power and simulation methodologies that now allow us to conduct in silico, computational experiments that circumvent wet lab constraints, opening novel ways to probe and uncover hidden aspects of actin dynamics not previously accessible. This project takes advantage of these improvements with a novel, systematic series of theoretical and computational studies of cytoskeletal dynamics using state-of-the-art simulation techniques and new approaches developed in the Principal Investigator laboratory. This project is divided into two scientific tasks that leverage our group’s expertise in physics. The first aim is to model all three main actin contraction mechanisms (filament buckling, polarity sorting, and depolymerization end-tracking) and ask under which conditions each becomes dominant over the others and when synergistic and antagonistic effects arise. Results from this task will serve as a guide to determine the underlying contraction mechanism in different cells and the degree to which different perturbations would enhance or impart its function. In the second aim the Principal Investigator will investigate how much force actin networks can produce, sustain over time, and transmit to adjacent networks. Current studies focus mostly on contraction rates, which does not provide a sufficient picture for the long-term effects of actin contraction. This new approach will help fill the gap between the cytoskeleton’s internal dynamics and large-scale cell behaviors. In addition, the Principal Investigator will also implement an educational plan consisting activities targeted to different groups: (i) a summer workshop on modelling cytoskeletal systems opened for the whole scientific community; (ii) a special topics course on physics of the cytoskeletal for seniors and graduate students at North Carolina State University; and (iii) a K-12 outreach activity to teach STEM concepts using archery. These three interrelated tasks are designed to address fundamental questions of high relevance in the physics of living systems. Completion of these tasks will provide a solid theoretical foundation of the inner workings of the actin cytoskeleton and pave the way for realistic models of in vivo systems, allowing us to study actin-associated cellular processes and diseases from a mechanistic point of view.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

生物的功能和发育取决于其细胞的不断活性。随着小胚胎的生长，细胞不断生长，分裂，迁移，改变形状并互相拉动。即使是成年人，我们的细胞仍会继续这些过程以维持身体功能并响应损伤。所有这些活动都取决于细胞产生和发射力的能力。肌动蛋白细胞骨架是每个细胞内部存在的小型动态细丝（肌动蛋白）和分子电动机的网状功能，是电源和跨组织和器官内部产生和传播的主要驱动力。所有细胞都需要功能性肌动蛋白细胞骨骼来维持其形状，并在发育过程中分裂为新细胞和驱动形状。 Without an optimally functional actin cytoskeleton, cells’ ability to migrate, differentiate, divide and respond to injury is compromised, leading to birth defects, cancers, fibrosis, immunodeficiencies, etc. To fully understand these processes, we need to first understand how the actin cytoskeleton works as a function of its components (motors, filaments and crosslinkers), and how it generates and transmits forces within and在细胞之间。必须从分子（底部）观点阐明肌动蛋白细胞骨架活动，以提供对其所有相关细胞过程的机械理解，并提供与细胞骨架功能障碍有关的新的治疗靶标。机理（皮质）及其在细胞分裂中的作用。但是，仅通过实验进行探测，必须解决的许多重要问题非常困难。其中包括：1）肌动蛋白2）什么使一种合同机制优于其他机制？ 3）网络可以产生多少力？ 4）相邻网络如何相互作用？幸运的是，最近有了显着改善计算机功率和仿真方法，这些方法现在使我们能够在硅胶中进行，这些计算实验可以规避湿实验室约束，开辟了新颖的方法来探测肌动蛋白动态的隐藏方面，以前无法访问。该项目利用最新的模拟技术和主要研究者实验室中开发的新方法对细胞骨架动力学进行了一系列新颖的，系统的理论和计算研究。该项目分为两项科学任务，以利用我们小组在物理学方面的专业知识。第一个目的是建模所有三种主要的肌动蛋白合同机制（细丝屈曲，极性排序和沉积端跟踪），并询问在哪些条件下均与其他条件占主导地位，以及何时出现协同和拮抗作用。该任务的结果将作为确定不同细胞中基本合同机制以及不同扰动会增强或赋予其功能的程度的指南。在第二个目标中，首席研究人员将研究肌动蛋白网络可以产生多少力量，随着时间的推移并传播到相邻网络。当前的研究主要集中在合同费率上，这对肌动蛋白收缩的长期影响没有足够的图像。这种新方法将有助于填补细胞骨架的内部动力学和大规模细胞行为之间的空白。此外，首席研究人员还将实施一项针对不同群体的活动的教育计划：（i）关于为整个科学界开放的夏季研讨会； （ii）北卡罗来纳州立大学的老年人和研究生细胞骨架物理学的特殊主题课程； （iii）K-12外展活动，以使用射箭来教授STEM概念。这三个相互关联的任务旨在解决生活系统物理学高相关性的基本问题。这些任务的完成将为肌动蛋白细胞骨架的内部运作提供稳固的理论基础，并为体内系统的现实模型铺平了道路，使我们能够从机制的角度研究与肌动蛋白相关的细胞过程和疾病，这是NSF的法定任务的综述，并通过评估了范围，从而弥补了这一范围。