Regulation of Cell Adhesions by Mechanical Force

该项目旨在了解生物材料如何响应机械力。粘附受体是质膜中介导细胞与其他细胞或细胞外基质结合的蛋白质。 这些受体感知并传递细胞与外部环境之间的力。 具体而言，整合素传递机械和生化信息。 这些信息对胚胎发育等生命过程起着关键性的指导作用，并且在癌症、高血压、骨质疏松症和动脉粥样硬化等疾病中也起着重要作用。整合素在生化信号或机械应力的作用下发生剧烈的长程变化。整合素氨基酸残基如何响应力而重排的确切方式在很大程度上是未知的，这是由于在单个蛋白质水平上观察残基位置和相互作用的变化存在技术挑战。 这阻碍了我们理解或调节这些可能导致疾病的过程的能力。本研究将运用细胞生物学、计算模拟、生物物理学、化学和材料科学等方法，从近原子水平上研究机械力对整合素构象的影响，以及由此产生的构象转变对细胞行为的调控作用。该研究小组将开发新的数值工具，以执行整合素在力作用下的分子动力学模拟。这些模型将用于预测稳定或不稳定特定整合素状态的突变，然后通过实验测试它们对活细胞中机械传感的影响。通过建模与实验相结合，我们将阐明力依赖性构象转变的详细途径及其在生物学中的作用。这种多学科方法将扩大不同社区和代表性不足的群体的参与，并对工程和材料科学教育产生积极影响。此外，这项研究可能会导致新的方法来设计和生产仿生和智能材料的工程应用。这个奖项反映了NSF的法定使命，并已被认为是值得通过评估使用基金会的智力价值和更广泛的影响审查标准的支持。

This project aims to understanding how biological materials respond to mechanical force. Adhesion receptors are proteins in the plasma membrane that mediate cell binding to other cells or to the extracellular matrix. These receptors sense and transmit forces between cells and the external environment. Specifically, integrins transmit mechanical and biochemical information. This information critically guides life processes such as embryonic development, and also plays a role in diseases such as cancer, hypertension, osteoporosis and atherosclerosis. Integrins undergo drastic, long-range changes in response to biochemical signals or mechanical stresses. Exactly how integrin amino acid residues rearrange in response to force is largely unknown due to the technical challenges in observing shifts in residue positions and interactions at the single protein level. This hampers our ability to understand or modulate these processes that can lead to disease. This research will employ cell biology, computational simulations, biophysics, chemistry and material science approaches to elucidate the detailed pathways of force-dependent changes in integrins conformation and their roles in cell regulation.The overarching objective of this research is to understand, at near-atomic level, how integrin conformation is modulated by mechanical force and how the resultant conformational transitions regulate cell behavior. The research team will develop new numerical tools to perform molecular dynamics simulations of integrins under force. These models will be used to predict mutations that stabilize or destabilize specific integrin states, which will then be tested experimentally for their effects on mechanosensing in live cells. By combining modeling with experiments, we will elucidate detailed pathways of force-dependent conformational transitions and their role in biology. This multidisciplinary approach will broaden the participation of diverse communities and underrepresented groups and positively impact engineering and material science education. Furthermore, this research may result in new approaches to design and produce biomimetic and smart materials for engineering applications.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.