Pathological consequences of altered tissue mechanics in fibrosis

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DESCRIPTION (provided by applicant): Cells respond to mechanical forces in their environment. These forces are likely to be as important to cell phenotype as soluble factors, with similarly complex effects. In particular, mechanical tension generated by cells in response to the stiffness of their environment regulates the behavior of most (if not all) cell types. Over the last ten years, the importance of matrix stiffness as a mechanism for modulating cell shape and function has become increasingly studied, and there is now good evidence that changes in stiffness not only correlate with disease, but contribute to its development. A limitation of most current work studying the role of tissue stiffness in pathology is an exclusive emphasis on cell and tissue elastic modulus, which is frequently reported as a constant independent of time or deformation (strain). Synthetic substrates have been used extensively for studies of the cellular response to substrate stiffness, but have a numberof significant differences from biological tissues: they are linearly elastic, whereas most biologicl materials demonstrate non-linearity~ they fail to incorporate viscosity, although biologicl materials are viscoelastic~ and they are two-dimensional rather than three-dimensional. Thus, while cells clearly respond to changes in the elastic modulus, the impact of viscosity and non-linearity on cells and tissues is not understood even though these factors may be major determinants of cell behavior in mechanically physiological environments. We hypothesize that mechanosensing by cells within tissues or on artificial substrates has characteristic length and time scales and that non-linear elasticity and viscosity are important properties of biological tissues that drive cell behavior and tissue organizaton over both short and long ranges. Our goal is to develop a mechanical model of a tissue, and to determine the biological relevance of various mechanical features to cell behavior and architectural features of this tissue when normal and injured. We will use the normal and fibrotic liver as a model tissue, since there are extensive preliminary characterizations of liver mechanics, although the general principles of our work will be applicable to multiple tissues. We have three specific aims: 1) to carry out a detailed mechanical characterization of the normal and fibrotic liver, and to develop and test a mechanical model of the liver highlighting the relative contributions of cells and the matrix~ 2) to develop and characterize novel viscoelastic substrates that mimic the viscoelasticity of normal and fibrotic livers, and to determine the response of individual cells of the liver to these biologically relevant substrates~ and 3) to computationally model and experimentally test the role of mechanics in large-scale tissue patterning in fibrosis.