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

作为对机械信号和力的响应，细胞使其细胞核变形，以执行诸如迁移、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。该项目集成了最先进的显微镜、分子力测量和理论生物物理学，以定量测量和建模允许细胞核对机械力做出反应和适应的纳米级过程。这项研究有望对核力学产生新的见解，并为广泛的研究应用提供测量细胞力的原创光学工具。对不同的早期职业科学家的培训是拟议项目的核心，为博士生、本科生和STEM高中生提供独特的物理和生物学交叉学科培训经验，并拥有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(LINC)复合体的纳米级结构和分子组织，这是细胞内核膜内的关键机械传递枢纽。它还将涉及开发新型光学力传感器，以定量地定义LINC复合体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互动，提供作为力感应中心的LINC复合体功能的物理模型。这项研究将通过一种高度多学科的方法来实施，该方法集成了超分辨率和寿命显微成像、纳米操纵、生物材料工程以机械地挑战细胞及其细胞核、开发用于机械生物学的新型传感器和理论建模。它将对正常和有缺陷的核功能的潜在机制产生基本的见解，并将对LINC复合体作为力传感和力转换装置进行定量描述。美国/法国的这个合作项目得到了美国国家科学基金会和法国国家科学基金会的支持，其中NSF资助美国的研究人员，ANR资助法国的合作伙伴。这一奖项反映了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。

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.