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Collaborative Research: Mechanobiology of Fiber Geometry-RhoGTPase Crosstalk at the Leading Edge of Cells Crawling on Fibers

合作研究：纤维几何力学生物学-在纤维上爬行的细胞前沿的 RhoGTPase 串扰

基本信息

批准号：
1762634
负责人：
Amrinder Nain
金额：
$ 44.2万
依托单位：
Virginia Polytechnic Institute and State University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2022-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1762634&HistoricalAwards=false
关键词：
Collaborative Research Mechanobiology Fiber Geometry

项目摘要

Cells move in a complex three-dimensional environment composed of fibrous proteins. A first step for a cell in choosing a direction to move is to sense its environment by tugging at the fibers. This starts what is called 'cell contractility.' How contractility is achieved on fibers of varying diameters distributed randomly or in specific patterns, in normal or diseased tissues, is mostly unknown. Understanding the first sensory interactions between a cell and a contacted fiber is important to how cells invade a fibrous tissue, such as when cancer cells leave a tumor, or in directed migration of cells on fibers towards a wound site. Most of what we know about cell migration stems from classical studies conducted on 2D flat substrates or, more recently, using complex gels. Neither approach allows the studying of cell-fiber interactions. This research will address the need to quantify cell-fiber interactions to understand cell migration during wound healing and disease. In this collaborative research, by combining state-of-art technologies in nanofiber manufacturing, cell signaling biosensors, and cell mechanics, we will be able to see inside the cell and determine the decision mechanisms that help cells migrate along fibers. The PI will work with faculty at a local community college to train them in the laboratory so that they can develop educational materials. This will create research opportunities for community college students.This project will define the mechanobiological state of a cell as it interacts with fibers. Specifically, we will reveal RhoGTPase signaling (RhoA, Rac1, and CdC42) as cells form protrusions and migrate on fibers. The interplay, localization, and summation of these molecules at specific regions of the cell define the mode of migration, which has been shown to be different in 2 and 3D. To determine the activity maps of these proteins in cells on fibers, we will design fiber networks of varying diameters (nanometers-microns) distributed in aligned and random configurations signifying pro- and anti-invasive conditions. In doing so, we will be able to pinpoint spatial and temporal activation maps of RhoGTPase's as cells tug and exert forces on fibers. The mechanobiological force quantitation-biosensor activation will develop new knowledge in the plasticity of cell migration to changing fibrous environments, as would be encountered in vivo. Linking adhesion receptor-based signaling spanning a wide range of spatial (nanometers-microns) and temporal (seconds-hours) scales with migration and force modulation will provide new knowledge in invasion-driven cell migration, thus opening new directions in drug discovery and development.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.

细胞在由纤维蛋白质组成的复杂三维环境中移动。细胞选择移动方向的第一步是通过拉扯纤维来感知环境。这就启动了所谓的“细胞收缩性”。“在正常或患病组织中，随机分布或以特定模式分布的不同直径的纤维如何实现收缩，大多数情况下是未知的。了解细胞和接触的纤维之间的第一感觉相互作用对于细胞如何侵入纤维组织（例如当癌细胞离开肿瘤时）或纤维上的细胞向伤口部位定向迁移非常重要。我们所知道的关于细胞迁移的大多数知识都来自于在二维平面基底上进行的经典研究，或者最近使用复合凝胶进行的研究。这两种方法都不允许研究细胞-纤维相互作用。这项研究将解决量化细胞-纤维相互作用的需求，以了解伤口愈合和疾病过程中的细胞迁移。在这项合作研究中，通过结合纤维制造、细胞信号生物传感器和细胞力学的最新技术，我们将能够看到细胞内部，并确定帮助细胞沿沿着纤维迁移的决定机制。 PI将与当地社区学院的教师合作，在实验室对他们进行培训，以便他们能够开发教育材料。这将为社区大学的学生创造研究机会。这个项目将定义细胞与纤维相互作用时的机械生物学状态。具体来说，我们将揭示RhoGT 3信号（RhoA，Rac 1和CdC 42）作为细胞形成突起和迁移纤维。这些分子在细胞特定区域的相互作用、定位和总和定义了迁移模式，这在二维和三维中是不同的。为了确定这些蛋白质在纤维上的细胞中的活性图，我们将设计不同直径（纳米-微米）的纤维网络，其以对齐和随机的配置分布，表示亲和抗侵入条件。在这样做的过程中，我们将能够精确定位RhoGTdR的空间和时间激活图，因为细胞在纤维上拖拽和施加力。力学生物力定量-生物传感器激活将开发新的知识，在可塑性的细胞迁移到不断变化的纤维环境，将在体内遇到。连接基于粘附受体的信号传导跨越广泛的空间范围，（纳米-微米）和时间具有迁移和力调节的（秒-小时）尺度将提供关于侵袭驱动的细胞迁移的新知识，这一奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查进行评估来支持的搜索.