Regulation of Cell Adhesions by Mechanical Force

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This project aims to understanding how biological materials respond to mechanical force. Adhesion receptors are proteins in the plasma membrane that mediate cell binding to other cells or to the extracellular matrix. These receptors sense and transmit forces between cells and the external environment. Specifically, integrins transmit mechanical and biochemical information. This information critically guides life processes such as embryonic development, and also plays a role in diseases such as cancer, hypertension, osteoporosis and atherosclerosis. Integrins undergo drastic, long-range changes in response to biochemical signals or mechanical stresses. Exactly how integrin amino acid residues rearrange in response to force is largely unknown due to the technical challenges in observing shifts in residue positions and interactions at the single protein level. This hampers our ability to understand or modulate these processes that can lead to disease. This research will employ cell biology, computational simulations, biophysics, chemistry and material science approaches to elucidate the detailed pathways of force-dependent changes in integrins conformation and their roles in cell regulation.The overarching objective of this research is to understand, at near-atomic level, how integrin conformation is modulated by mechanical force and how the resultant conformational transitions regulate cell behavior. The research team will develop new numerical tools to perform molecular dynamics simulations of integrins under force. These models will be used to predict mutations that stabilize or destabilize specific integrin states, which will then be tested experimentally for their effects on mechanosensing in live cells. By combining modeling with experiments, we will elucidate detailed pathways of force-dependent conformational transitions and their role in biology. This multidisciplinary approach will broaden the participation of diverse communities and underrepresented groups and positively impact engineering and material science education. Furthermore, this research may result in new approaches to design and produce biomimetic and smart materials for engineering applications.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.