NSF-ANR: DynamoLINC: Dynamics, Nanoscale Organization and Modeling of LINC Under Mechanical Stress

在机械提示和力的作用下，细胞会使细胞核变形以执行迁移、基因表达或细胞命运决定等关键功能，但力感知和适应性核形状变形的基本生物物理机制仍不清楚。该项目整合了最先进的显微镜、分子力测量和理论生物物理学，以定量测量和模拟纳米尺度的过程，使细胞核能够响应和适应机械力。这项研究有望为核力学和原始光学工具提供新的见解，以测量细胞力，用于广泛的研究应用。培养不同的早期职业科学家是拟议项目的核心，为博士生、本科生和STEM高中学生提供物理和生物学交叉的独特跨学科培训经验，并提供研究生命系统模式的专业知识。该项目将建立核骨架和细胞骨架连接物（LINC）复合物的纳米级结构和分子组织，这是细胞核膜内至关重要的机械转导中心。它还将涉及新型光学力传感器的开发，以定量地定义LINC复合物对核膜上特定力的结构适应性。它还将通过理论和实验的密切相互作用，提供作为力传感中心的LINC复杂功能的物理模型。该研究将通过高度多学科的方法来实施，包括超分辨率和终身显微镜成像，纳米操作，生物材料工程，机械挑战细胞及其细胞核，机械生物学和理论建模的新型传感器的发展。它将对正常和有缺陷的核功能的机制产生基本的见解，并将对LINC复合物作为力传感和力传感装置进行定量描述。这个美国/法国合作项目由美国国家科学基金会和法国国家研究机构支持，其中美国国家科学基金会资助美国研究者，法国国家研究机构资助法国合作伙伴。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

In response to mechanical cues and forces, cells deform their nucleus to perform critical functions such as migration, gene expression or cell fate decision, but the fundamental biophysical mechanisms underlying force sensing and adaptive nuclear shape deformation remain elusive. This project integrates state-of-the-art microscopies, molecular force measurements and theoretical biophysics to quantitatively measure and model the nanoscale processes allowing the cell nucleus to respond and adapt to mechanical forces. The research is expected to yield novel insights into nuclear mechanics and original optical tools to measure cellular forces for a broad range of research applications. Training of diverse early career scientists is central to the proposed project, providing Ph.D. students, undergraduate and STEM high-school students with a unique interdisciplinary training experience at the intersection of physics and biology and with expertise in studying the patterns in living systems.The project will establish the nanoscale structural and molecular organizations of the Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes, which serve as crucial mechanotransducing hubs within the nuclear envelope in cells. It will also involve the development of novel optical force sensors to quantitatively define the architectural adaptability of LINC complexes in response to specific forces at the nuclear membrane. It will additionally provide physical models of LINC complex functions as force-sensing centers, via a close interplay of theory and experiments. The research will be implemented through a highly multidisciplinary approach that integrates super-resolution and lifetime microscopy imaging, nanomanipulation, engineering of biomaterials to mechanically challenge cells and their nucleus, the development of novel sensor for mechanobiology and theoretical modeling. It will generate fundamental insights into the mechanisms underlying normal and defective nuclear functions and will yield quantitative descriptions of the LINC complex as a force sensing and force transducing apparatus. This collaborative US/France project is supported by the US National Science Foundation and the French Agence Nationale de la Recherche, where NSF funds the US investigator and ANR funds the partners in France.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.