A Multiscale Material Approach to Understanding the Effects of Viscoelasticity on Cell Adhesion, Migration, and TGF-beta Activation/Signaling

了解粘弹性对细胞粘附、迁移和 TGF-β 激活/信号传导影响的多尺度材料方法

• 批准号: 1825398
• 负责人: Ashley Brown
• 金额: $ 40万
• 依托单位: North Carolina 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: 2018-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1825398&HistoricalAwards=false
• 关键词: Multiscale; Material; Approach; Understanding; Effects

Cells are able to sense and react to changes in the mechanical properties of their microenviroment through a process known as mechanotransduction. The effect of the surrounding environment affects cell attachment, migration, proliferation, and differentiation. However, most tissues that include cells do not behave in a simple, elastic fashion. In fact, their properties are generally non-linear and viscoelastic -- meaning that they vary as the tissue is stretched and based on how quickly the force or stretch is applied. Significant research effort is being conducted into the best ways to get cells to develop into healthy tissues for tissue replacement or enhancement. Understanding how cells respond to their surroundings is key to being able to design systems that will optimize these engineered tissues. This project will focus on the effect of the viscoelastic properties of a substrate -- its ability to dissipate energy based on how quickly the force is applied -- on the clustering of a cellular receptor for a common growth factor (TGF-Beta) as well as how cells respond downstream to signals that are generated. In addition to the scientific impact, the project team will focus on training students in a multidisciplinary environment so that they can in the future work effectively on interdisciplinary teams to tackle complex problems at the interface of engineering, materials science, and biomedical science.In order to investigate the nonlinear, viscoelastic substrate variation on fibroblast behavior, three objectives have been established. First, to determine how the viscoelasticity of a developed microgel, colloidal thin film influences fibroblast adhesion, spreading, migration, and myofibroblastic differentiation. Second, to analyze TGF-Beta receptor clustering, activation, and signaling as a function of microgel film viscoelasticity. And, finally, to examine the effect of pre-patterning TGF-Beta receptors on the substrate via DNA origami on cell adhesion, spreading, migration, and myofibroblastic differentiation. The studies will provide new insights into how cells respond to changes in viscoelasticy in their microenvironment.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.

细胞能够通过一个称为机械转导的过程来感知其微环境的机械特性变化并做出反应。周围环境的作用影响细胞的附着、迁移、增殖和分化。然而，包括细胞的大多数组织并不以简单的弹性方式表现。事实上，它们的特性通常是非线性和粘弹性的-这意味着它们随着组织的拉伸而变化，并且基于施加力或拉伸的速度。 正在进行大量的研究工作，以获得细胞发育成健康组织的最佳方法，以进行组织替代或增强。了解细胞如何对周围环境做出反应是能够设计优化这些工程组织的系统的关键。该项目将专注于基板的粘弹性特性的影响-它的能力耗散能量的基础上如何快速施加力-对一个共同的生长因子（TGF-β）的细胞受体的集群，以及细胞如何响应下游产生的信号。除了科学影响之外，该项目团队还将重点培养学生在多学科环境中的能力，以便他们在未来能够有效地在跨学科团队中工作，以解决工程，材料科学和生物医学科学的界面上的复杂问题。为了研究非线性粘弹性基质变化对成纤维细胞行为的影响，确定了三个目标。首先，要确定一个发达的微凝胶，胶体薄膜的粘弹性如何影响成纤维细胞的粘附，扩散，迁移和肌纤维母细胞分化。第二，分析TGF-β受体聚集、活化和信号传导作为微凝胶膜粘弹性的函数。最后，研究通过DNA折纸在基质上预图案化TGF-β受体对细胞粘附、扩散、迁移和成肌纤维细胞分化的影响。这些研究将为细胞如何应对微环境中粘弹性的变化提供新的见解。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Viscoelastic properties of microgel thin films control fibroblast modes of migration and pro-fibrotic responses

• DOI: 10.1016/j.biomaterials.2018.09.012
• 发表时间: 2018-12-01
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Chester, Daniel;Kathard, Rahul;Brown, Ashley C.
• 通讯作者: Brown, Ashley C.