MSM-Multi-scale Analysis of Cellular Force Transmission and Biochemical Activatio

Massachusetts Institute Of Technology, Cambridge MA

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Abstract

DESCRIPTION (provided by applicant): Numerous cellular processes occur at the interface between mechanics and biology. Such responses can range from changes in cell morphology to activation of signaling cascades to changes in cell phenotype. Although the biochemical signaling pathways activated by mechanical stimulus have been extensively studied, little is known of the basic mechanisms by which mechanical force is transduced into a biochemical signal, or how the cell changes its behavior or properties in response to external or internal stresses. While the approach proposed here has a computational emphasis, ongoing experiments will help to motivate and validate the computational studies. For example, studies have examined the change in internal structure that occurs when a neutrophil enters a capillary. An immediate reduction in stiffness is observed, followed by a progressive increase, sometimes leading to active protrusion. Mechanical deformation in this example initiates remodeling of the cell interior, activating signaling pathways that may or may not lead to a migratory response. Another example involves biochemically mediated reorganization of the intermediate filament network in the Panc-1 human pancreatic cancer cell which results in a 3-fold reduction in the stiffness of the cell and a marked increase in the hysteresis in mechanical deformation; both of these factors are considered to facilitate cell mobility and cancer metastasis. The ultimate goal in this research is to capture such phenomena through quantitative modeling and simulation and use the results in developing new insights into the disease process and ultimately, new therapies. The primary aim of this project is to develop a broad but rigorous computational framework that links mechanical forces to conformational changes in single proteins by coupling biochemical activity with molecular dynamics simulations of protein deformation in a fully three-dimensional (3D) filamentous network. The prototypical problem is the simulation of cytoskeletal rheology and remodeling. Our specific aims are to: 1. Develop separate computational approaches at the nano-, meso-, and macro-scales, using molecular dynamics, Brownian dynamics, and finite element methods to simulate the mechanical and biochemical activity responsible for cytoskeletal rheology. 2. Construct and make available to the research community multi-scale algorithms that enable direct communication between the different computational platforms. 3. Extend this simple model to incorporate multiple reactions and to include the effects of signaling pathways necessary for models of mechanotransduction and cell migration. 4. Conduct experiments in reconstituted actin networks to provide a pheonological basis for evaluation and evalidation of the computational models.