The Role of Cellular Mechanical Oscillations in Triggering Cell Migration

该奖项将研究广泛存在于许多细胞类型中的细胞机械振荡。在迁移细胞(能够从身体的一个位置移动到另一个位置的细胞)中，细胞的机械振荡被认为通过触发细胞迁移而导致疾病的发展，如心血管疾病和癌症。然而，在理解这些细胞机械振荡是如何调节的，从而触发细胞迁移方面，存在着一个关键的差距。这种知识鸿沟的持续存在阻碍了预防和治疗人类疾病的疗法的发展。本研究旨在阐明细胞机械振荡的分子机制及其在细胞迁移中的作用。这项工作的科学成果有望推动治疗和预防与细胞迁移相关的疾病的努力。这项工作还促进了南达科他州生物工程的本科生和研究生教育和培训。将向来自STEM历史上代表性不足的本科生提供指导和真实的研究经验。特别是，将与当地一所部落学院和一所以本科为主的机构合作，推进一个以发现为基础的项目，以吸引美国原住民、女性和第一代学生从事生物医学工程领域的职业生涯。这项工作回答了一个中心问题：细胞机械振荡的潜在机制和功能是什么，物理化学刺激是如何调节它们的？假设细胞机械振荡是由细胞骨架重塑和细胞粘附力的振荡驱动的，而细胞粘附力的重塑和振荡反过来又协同调节细胞的极化和迁移。这一假设将通过三个研究目标来解决。首先，这项工作将破译细胞骨架重塑和纽蛋白振动驱动细胞力学周期性振荡的潜在机制。其次，这项工作将阐明细胞力学中的振荡、极化和迁移之间的关系。第三，这项工作将发现物理化学信号如何调节细胞机械振荡和细胞迁移。采用了一种创新的方法，其中包括：(A)实时荧光寿命成像显微镜监测细胞骨架动力学；(B)使用原子力显微镜监测细胞机械振荡和细胞膜波动的实时E模图和高度图；以及(C)用于信号和图像处理的数据驱动的数学模型。这项研究首次将细胞机械振荡与细胞膜波动、细胞极化，然后与细胞迁移联系起来。预计这一发现将提供对细胞机械振荡的根本新理解，并为治疗人类疾病(如心血管疾病和癌症转移)的新策略的开发提供信息。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This award will study cellular mechanical oscillations, which exist broadly in many cell types. In migrating cells (cells that are able to move from one location of the body to another), mechanical oscillations of cells are thought to contribute to disease development, such as cardiovascular disease and cancer by triggering cell migration. However, a critical gap exists in understanding how these cellular mechanical oscillations are regulated, and thus trigger cell migration. Continued existence of this knowledge gap hinders the development of therapies to prevent and treat human disease. This study seeks to elucidate the molecular mechanism of cellular mechanical oscillations and their functions in cell migration. Scientific outcomes of this work are expected to advance efforts to treat and prevent cell migration-relevant diseases. This work also advances undergraduate and graduate education and training in bioengineering in South Dakota. Mentoring and authentic research experiences will be provided to undergraduate students from groups historically underrepresented in STEM. In particular, in collaboration with a local tribal college and a primarily undergraduate institution, a discovery-based program will be advanced to attract Native American, female, and first-generation students to pursue careers in biomedical engineering. This work answers a central question: What is the underlying mechanism and function of cellular mechanical oscillations, and how do physicochemical stimuli regulate them? The hypothesis is cellular mechanical oscillations are driven by cytoskeletal remodeling and oscillation in cell adhesion force, which, in turn, synergistically regulates cell polarization and migration. This hypothesis will be addressed by three research objectives. First, the work will decipher the underlying mechanism by which cytoskeletal remodeling and vinculin vibration drive periodic oscillations in cell mechanics. Second, the work will elucidate the relationship between oscillations in cell mechanics, polarization, and migration. Third, the work will discover how physicochemical signals regulate cellular mechanical oscillations and cell migration. An innovative approach is employed that integrates: (a) real-time fluorescence-lifetime imaging microscopy to monitor cytoskeleton dynamics; (b) real-time cellular E-modulus-mapping and height-mapping using atomic force microscopy to monitor cellular mechanical oscillations and cell membrane undulation; and (c) data-driven mathematical models for signal and image processing. For the first time, this study will link cellular mechanical oscillations to cell membrane undulation, cell polarization, and then to cell migration. Findings are expected to provide fundamental new understanding of cellular mechanical oscillations and inform development of new strategies to treat human disease, such as cardiovascular disease and cancer metastasis.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.