The Role of Distributed Foci of Tissue Stiffness in Cell-Cell Adhesion

组织硬度分布灶在细胞间粘附中的作用

• 批准号: 1738345
• 负责人: Cynthia Reinhart-King
• 金额: $ 24.32万
• 依托单位: Vanderbilt University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1738345&HistoricalAwards=false
• 关键词: Role; Distributed; Foci; Tissue; Stiffness

The tissues of the body stiffen with age and also with the progression of numerous diseases. It is now known that this change in stiffness can drive disease by causing cells within the tissue to adopt unhealthy behaviors. However, tissues do not stiffen uniformly. The tissues can develop numerous small foci of stiffness so that the stiffness varies markedly throughout. It is not yet known how cells respond to these distributed foci of stiffness that develop with age and disease. This award supports the research necessary to understand how the process of aging contributes to the development of stiffness foci and how these stiff foci alter cell function. The primary activity in this work will be on the development of mechanical stiffness foci within blood vessels and the evaluation of their effects on the cells within the blood vessel wall. However, this basic research will have a broad impact on current understanding of physiology and pathology throughout the body, as changes in tissue stiffness with age can occur in multiple different organ systems. As such, this work will have broad impact to society. The project involves techniques from cell biology, materials science, optics, and microfabrication. This multi-disciplinary approach coupled with research activities designed to involve diverse sets of researchers and students will help train engineers to think and work across disciplinary boundaries.While "heterogeneity" is now appreciated as an important component of biology, the primary focus to-date has been on cell-to-cell molecular-level heterogeneities. However, heterogeneities also exist in the extracellular environment and have been largely overlooked. Many tissues display foci of mechanical stiffness - heterogeneities in stiffness that exist over just a few microns. This project will address the stiffness foci that develop in tissue and their effects on cell-cell adhesion and force generation. In this project, the major research goal is to characterize these foci and their biophysical effects on endothelial cell-cell adhesion using state-of-the-art tools including Atomic Force Microscopy (AFM), microfabrication, and ex vivo models. These studies have the potential to identify a novel mechanism by which age contributes to endothelial dysfunction. More importantly, this work will bring to light the role of mechanical heterogeneities within the matrix on cell biophysics. While the research here will be on the endothelium, it is expected that the results will be relevant to many tissues and pathologies including cancer and embryonic development where heterogeneities in mechanical properties also exist.

身体的组织随着年龄的增长而变硬，也随着各种疾病的发展而变硬。现在已经知道，这种僵硬的变化会导致组织内的细胞采取不健康的行为，从而导致疾病。然而，组织并不会均匀地变硬。组织可以形成许多小的僵硬灶，因此整个组织的僵硬程度有很大的变化。目前尚不清楚细胞对这些随年龄和疾病发展的分布的僵硬灶有何反应。该奖项支持必要的研究，以了解衰老过程如何有助于僵硬焦点的发展，以及这些僵硬焦点如何改变细胞功能。这项工作的主要活动将是发展血管内的机械僵硬灶，并评估其对血管壁内细胞的影响。然而，这项基础研究将对目前对整个身体的生理学和病理学的理解产生广泛的影响，因为组织硬度随年龄的变化可能发生在多个不同的器官系统中。因此，这项工作将产生广泛的社会影响。该项目涉及细胞生物学、材料科学、光学和微制造技术。这种多学科的方法，再加上旨在让不同的研究人员和学生参与的研究活动，将有助于培训工程师跨学科边界思考和工作。虽然现在“异质性”被认为是生物学的一个重要组成部分，但迄今为止的主要重点一直是细胞到细胞分子水平的异质性。然而，细胞外环境中也存在异质性，这在很大程度上被忽视了。许多组织显示出机械硬度的病灶--硬度的异质性仅存在于几微米以上。这个项目将解决在组织中形成的僵硬焦点及其对细胞-细胞黏附和力产生的影响。在这个项目中，主要的研究目标是利用包括原子力显微镜(AFM)、微细加工和体外模型在内的最先进的工具来表征这些病灶及其对内皮细胞-细胞黏附的生物物理效应。这些研究有可能确定AGE促进内皮功能障碍的新机制。更重要的是，这项工作将揭示基质中的机械异质性对细胞生物物理学的作用。虽然这里的研究将是关于内皮的，但预计结果将与许多组织和病理相关，包括癌症和胚胎发育，在这些组织和病理中，机械性能也存在异质性。