Force is ubiquitous in nature and physical stimuli are crucial for cell function. How cells process forces determines key physiological processes such as cell growth and differentiation, in which cells divide or differentiate according to the chemical and physical cues cells receive from the extracellular matrix. Physical stimuli have also been involved in the development of pathological processes, especially those in which cells lose the proper physical communication with the environment, such as cancer and metastasis formation. The major components of the mechanotransduction signaling pathways that transmit and translate these physical messages will most likely to be the molecules that directly sense force from the extracellular matrix. These molecules are integrins and the proteins that link them to the cytoskeleton. Here, I propose a multidisciplinary approach aimed to elucidate how force can modulate cellular behaviour. The project will focus on (i) determining how cells sense, produce and interpret forces and (ii) the cellular outcomes resulting from these processes. First, a nanotechnological suite composed of magnetic tweezers, and siRNA technology will be developed and employed to determine the roles of the molecules involved in these mechanical pathways. Second, the molecular mechanisms that trigger the interaction of proteins under force application will be studied. Several biophysical techniques such as magnetic tweezers, Atomic Force Microscopy (AFM), Total Internal Reflection Fluorescence (TIRF), and Fluorescence Resonance Energy Transfer (FRET) will be used here. Finally, a comparative study of the effect of force in normal and malignant cells will be accomplished. It will be tested whether or not these pathways are involved in the expression of genes in the nucleus, and the ability of normal and malignant cells to respond to external forces and to apply forces on their substrates. Magnetic tweezers, and elastic pillars will be used here.
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Funding SchemeERC-SG - ERC Starting Grant