Elucidating the Role of Mechanosensitive Signaling in Mediating Cell-Biomaterial Interactions

从根本上说，生物材料研究的进步是由诱导所需细胞的能力驱动的。 通过开发有指导意义的生物材料表面来实现行为。新型生物材料的合理设计 能够成功地操纵细胞行为使其发挥特定功能的方法， 有启发性的线索和对这些线索如何改变细胞功能的机械理解。然而，在这方面， 确定线索的特定组合以诱导导致细胞行为的精确集合， 可预测的功能结果仍然具有挑战性。这一挑战源于对以下问题的不完全理解： 细胞用来检测和响应环境线索的机制，特别是物理线索， 细胞形状的限制或细胞外环境的硬度。物理线索是通过 机械转导，一个知之甚少的过程，通过该过程细胞将物理刺激转化为 生化检测信号机械传导研究的最新进展已经分离出一个关键的 粘着斑蛋白黏着斑蛋白的作用，黏着斑蛋白是细胞间机械连接的重要联系， 细胞外环境和产生力的肌动蛋白细胞骨架。该提案旨在评估 假设细胞感觉到细胞-生物材料界面的物理性质的不同变化， 黏着斑蛋白的不同机械负载，导致细胞信号传导途径的激活。具体来说，我们将 研究细胞形状、细胞大小和细胞外蛋白质对力敏信号激活的影响。的 拟议的工作与NIH的使命有关，因为它将增加对细胞如何 对周围环境的物理方面做出感知和反应。这将为以下方面的进展奠定基础： 生物材料设计以及帮助理解与物理缺陷相关的疾病状态的努力， 细胞环境的性质，如癌症和过度的组织纤维化。

At a fundamental level, advances in biomaterials research are driven by the ability to elicit desired cell behaviors through the development of instructive biomaterial surfaces. Rational design of novel biomaterials that can successfully manipulate cell behavior toward a specific function requires both identification of instructive cues and a mechanistic understanding of how these cues alter cellular function. However, determining the specific combination of cues to induce a precise set of cellular behaviors leading to a predictable functional outcome remains challenging. The challenge stems from an incomplete understanding of the mechanisms used by cells to detect and respond to environmental cues, particularly physical cues such as confinement of cell shape or stiffness of the extracellular environment. Physical cues are detected through mechanotransduction, a poorly understood process through which cells convert physical stimuli into biochemically detectable signals. Recent advances in the study of mechanotransduction have isolated a key role for the focal adhesion protein vinculin, an important linkage in the mechanical connections between the extracellular environment and the force-generating actin cytoskeleton. This proposal seeks to evaluate the hypothesis that cells sense diverse changes in the physical nature of the cell-biomaterial interface through distinct mechanical loading of vinculin, leading to the activation of cell signaling pathways. Specifically, we will study the effects of cell shape, cell size, and extracellular proteins on force-sensitive signal activation. The proposed work is relevant to the mission of NIH as it will increase the fundamental understanding of how cells sense and respond to the physical aspects of their surroundings. This will lay the foundation for advances in biomaterials design as well as aid efforts to understand disease states associated with defects in the physical nature of the cellular environment, such as cancer and excessive tissue fibrosis.