NSF-ANR MCB/PHY - MechaLINC: Mechanistics of LINC-mediated force transmission

About This Grant

Cells receive many signals from their environment, including tensions and mechanical forces that are transferred all the way down to their nucleus. Nuclear shape adaptations to those forces are critical for cell fate and function. Yet, the physical and molecular principles underlying those adaptive mechanisms remain largely undefined. By integrating state-of-the-art scientific approaches, this project will generate mechanistic understandings of nuclear mechanics and predictive insights into the organization of force-transmitting complexes in human cells. The work will offer novel rationales to design bio-inspired and force-responsive nanodevices for human health. It will also contribute new perspectives on the normal and defective mechanobiology of the nucleus, advancing our understanding of those critical cellular processes and the diseases that are caused by dysfunction in these systems. A key aspect of the project is the training of early-career scientists, graduate students, undergraduates, and STEM-focused high school students to expose them to a unique research experience at the crossroads of physics and biology. The project will probe and define the physical mechanisms of force transmission at the Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes. These complexes are assemblies of proteins, which exhibit low elastic moduli on their own, but that collectively function as mechanotransducing hubs capable of conveying forces across the membrane of the nucleus, via mechanisms that remain poorly understood. The goals are to identify the molecular tenants governing the formation, maintenance and disassembly of LINC protein clusters as a function of forces applied on the nucleus, to measure forces exerted at these clusters with fluorescent optical force sensors and to formulate physical models that define how LINC complex clustering participates to local changes in the shape of the nuclear membrane and force transmission. The project will integrate theory and experiment. It will be implemented through a multidisciplinary approach involving super-resolution microscopy, single molecule tracking, FRET imaging, cellular nanomanipulation, engineering of novel optical force sensors, their calibration using DNA origami nanoactuators, and theoretical modeling. The project will lead to a better understanding the mechanical properties of the nucleus, its membrane and cell mechanics in general. 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.