CAREER: Biomechanics and Mechanobiology of Vimentin Intermediate Filaments

该学院早期职业发展（CAREER）奖将支持研究波形蛋白中间丝在细胞运动和核稳定性中的生物力学作用。适当的细胞运动对于伤口愈合、发育和正常组织维持是必要的。细胞必须足够灵活，以移动和遵守外部物理应力，但足够强大，以保持形状和结构的完整性。因此，虽然软细胞核有助于细胞通过组织中的小孔迁移，但所产生的物理应力（如果不减轻）可导致核损伤和致病性病症。波形蛋白是许多迁移细胞的细胞骨架成分，对核定位和核稳定性很重要。然而，波形蛋白是如何独特地保护细胞核的，在很大程度上仍然是未知的。这项研究将探索波形蛋白如何使细胞感知和响应机械应力。这项工作的结果揭示了控制细胞迁移的机械和生物信号。这项研究得到了一项综合教育和外联计划的补充。该计划旨在通过以下方式吸引和培训学生来拓宽STEM途径：1）一种新颖的开放式牵引力显微镜工具，2）一门新颖的课程，物理学和STEM的公众参与。来自锡拉丘兹市学区的高中生将参与这两项外展活动。本项目的总体研究目标是揭示细胞骨架聚合物波形蛋白稳定受限细胞迁移的生物物理机制及其在加强适当核转位中的作用。该研究围绕三个目标组织：1）确定波形蛋白在核形状和变形性中的作用，2）定义波形蛋白如何在3D迁移期间建立全细胞极化和牵引应力，以及3）探索波形蛋白在与细胞对压缩力的反应相关的机械转导途径中的作用。这项工作的发现将为通过基本细胞迁移过程推进的健康组织维持和疾病进展机制提供重要的新见解。从长远来看，项目成果将提出新的策略，以帮助伤口愈合过程中的细胞运动，以及破坏病理环境中的异常细胞运动和核损伤，如纤维化和癌症。该奖项反映了NSF的法定使命，并已被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

This Faculty Early Career Development (CAREER) award will support research to investigate the biomechanical role of vimentin intermediate filaments in cell motility and nuclear stability. Proper cell motility is necessary for wound healing, development, and normal tissue maintenance. Cells must be flexible enough to move and comply with external physical stresses yet strong enough to maintain shape and structural integrity. Thus, while a soft cell nucleus is conducive to cell migration through small pores in tissue, the resulting physical stress (if not mitigated) can lead to nuclear damage and pathogenic conditions. Vimentin is a cytoskeletal component of many migrating cells and is important to nuclear positioning and nuclear stability. However, how vimentin is uniquely able to protect the nucleus is still largely unknown. This research will explore how vimentin enables cells to sense and respond to mechanical stresses. The results of this work shed light on the mechanical and biological signals that control cell migration. This research is complemented by an integrated educational and outreach plan. This plan aims to broaden STEM pathways by attracting and training students through 1) a novel open-access traction force microscopy tool, and 2) a novel course, Public Engagement in Physics and STEM. High school students from Syracuse City School Districts will engage in both outreach activities.The overall research goal of this project is to uncover the biophysical mechanisms by which the cytoskeletal polymer vimentin stabilizes confined cell migration and its role in reinforcing proper nuclear translocation. The study is organized around three objectives: 1) determining the role of vimentin in nuclear shape and deformability, 2) defining how vimentin establishes whole cell polarization and traction stress during 3D migration, and 3) probing vimentin’s role in mechanotransduction pathways associated with cellular response to compressive forces. The findings from this work will provide important new insight into mechanisms of healthy tissue maintenance and disease progression that advance through fundamental cell migration processes. In the longer-term, project outcomes will suggest new strategies to aid cell motility during wound healing as well as disrupt abnormal cell motility and nuclear damage in pathological contexts, such as fibrosis and cancer.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.