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

NSF-ANR：DynamoLINC：机械应力下 LINC 的动力学、纳米级组织和建模

基本信息

批准号：
2202087
负责人：
Fabien Pinaud
金额：
$ 68.74万
依托单位：
University of Southern California
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2202087&HistoricalAwards=false
关键词：
NSF ANR DynamoLINC Dynamics Nanoscale

项目摘要

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.

为了响应机械信号和力，细胞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，但力传感和适应性核形状变形背后的基本生物物理机制仍然难以捉摸。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，以定量测量和模拟纳米级过程，使细胞核能够响应和适应机械力。该研究预计将对核力学和原始光学工具产生新的见解，以测量细胞力，以适应广泛的研究应用。对不同的早期职业科学家的培训是拟议项目的核心，提供博士学位。学生、本科生和 STEM 高中生，在物理和生物学交叉领域拥有独特的跨学科培训经验，并具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连接器的纳米级结构和分子组织（LINC）复合物，作为细胞核膜内重要的机械传导中枢。它还将涉及新型光学力传感器的开发，以定量定义 LINC 复合物响应核膜上特定力的结构适应性。它还将通过理论和实验的紧密相互作用，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，该方法集成了超分辨率和寿命显微镜成像、纳米操作、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和理论建模的新型传感器。它将产生对正常和有缺陷的核功能背后机制的基本见解，并将产生对 LINC 复合体作为力传感和力转换装置的定量描述。这个美国/法国合作项目得到了美国国家科学基金会和法国国家研究机构的支持，其中 NSF 资助美国研究人员，ANR 资助法国合作伙伴。该奖项反映了 NSF 的法定使命，并被认为值得支持通过使用基金会的智力优点和更广泛的影响审查标准进行评估。