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

University Of Southern California, Los Angeles CA

Investigators

Abstract

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.