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

身体的组织随着年龄的增长和许多疾病的发展而变硬。现在我们知道，这种硬度的变化可以通过导致组织内的细胞采取不健康的行为来驱动疾病。然而，组织并不是均匀硬化的。组织可形成许多小的僵硬灶，因此僵硬度在整个过程中变化明显。目前尚不清楚细胞如何对这些随年龄和疾病发展的分布性僵硬灶作出反应。该奖项支持必要的研究，以了解衰老过程如何促进僵硬灶的发展，以及这些僵硬灶如何改变细胞功能。这项工作的主要活动将是血管内机械刚度焦点的发展和评估它们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和病理的理解产生广泛的影响，因为随着年龄的增长，组织硬度的变化可能发生在多个不同的器官系统中。因此，这项工作将对社会产生广泛的影响。该项目涉及细胞生物学、材料科学、光学和微加工技术。这种多学科的方法与研究活动相结合，旨在让不同的研究人员和学生参与其中，这将有助于培养工程师跨越学科界限的思考和工作。虽然“异质性”现在被认为是生物学的一个重要组成部分，但迄今为止主要关注的是细胞间分子水平的异质性。然而，异质性也存在于细胞外环境中，并且在很大程度上被忽视了。许多组织表现出机械刚度的焦点-刚度的不均匀存在于仅仅几微米。该项目将解决组织中发展的僵硬焦点及其对细胞粘附和力产生的影响。在这个项目中，主要的研究目标是利用最先进的工具，包括原子力显微镜（AFM）、微加工和离体模型来表征这些病灶及其对内皮细胞-细胞粘附的生物物理效应。这些研究有可能确定年龄导致内皮功能障碍的新机制。更重要的是，这项工作将揭示基质内机械异质性在细胞生物物理学中的作用。虽然这里的研究将集中在内皮上，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，这些组织和病理也存在机械性能的异质性。

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.