CAREER: The Function of Nuclear-Cytoskeletal Tethers in Cell Mechanosensing

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The research objective of this Faculty Early Career Development (CAREER) award consists of answering an important, fundamental question: how does mechanical connectivity between the nucleus and the cytoskeleton control key cell functions like cell mechanosensing, cell motility and cell adhesion? Mechanical forces control the in vivo development of tissues and are crucial for the in vitro development of tissue substitutes like artificial arteries and tissue-engineered heart valves. The molecular mechanisms by which cells sense mechanical stimuli and transduce them into signaling responses are not well-understood. The research approach combines engineering techniques to apply controlled mechanical stimuli to cells, with molecular biology techniques to interfere with the function of nesprin proteins that physically link the nucleus and the cytoskeleton. The following objectives are proposed: 1) Determine the mechanism by which nesprin family proteins control cell sensing of applied forces. 2) Test the hypothesis that nuclear-cytoskeletal linkages regulate cell sensing of substrate rigidity. 3) Determine the extent to which nesprins transfer mechanical force between the nucleus and the cytoskeleton. This work will lead to improved understanding of tissue development where mechanical forces control developmental gene expression, embryogenesis and tissue patterning. The proposed research will develop molecular-level understanding of cell mechanosensing. Consequently, it will aid the success of engineering strategies which use mechanical forces for developing tissue substitutes with improved performance. Given the ever-growing need for tissue substitutes, this research has strong potential for benefitting society. The educational program will impact students at different levels over the award period including middle and high school students, and undergraduate students from under-represented groups.