Mathematical Modeling and Computational Analysis of Cell and Tissue Movement

University Of Minnesota-Twin Cities, Minneapolis MN

Investigators

Abstract

The overall objective of this project is to develop a multiscale model of cell motility that incorporates processes ranging from the molecular/filament scale to the whole-cell scale. We shall do this by developing microscopic filament-based models for force generation at the leading edge, and then integrating these into a continuum description. We will develop modules for the subprocesses that can be tested separately on different systems and then integrated into the complete model. This approach is necessary, given the complexity of the problem, but is also the best long-term strategy because it will allow for the use of different modules for different systems, and facilitate incorporation of new information as it becomes available. A summary of the major steps is as follows. We will formulate an integrated microscopic model of force generation in a simple geometry and obtain the force velocity relation, then apply this to a number of different experimental configurations. We will then develop the continuum description for actin dynamics and force generation and test it on data for retrograde flow in coelomocytes and apply it, suitably modified, to the actin comet tail in the pathogenic bacterium Listeria monocytogenes. All phases will require the development of appropriate computational tools. Cell movement is an essential process at various stages in the life cycle of most organisms: early development of multicellular organisms involves individual and collective cell movement, leukocytes must migrate toward sites of infection as part of the immune response, and in cancer directed movement is involved in invasion and metastasis. Movement entails force generation within cells and mechanical interactions with their surroundings, and understanding how they are controlled in space and time to produce cell-level movement is a major challenge. The complexity of the molecular network that controls these processes is such that not all interactions can be followed at the molecular level in a computational model; a multiscale hybrid of microscopic and continuum descriptions is needed. At present there is no multiscale three-dimensional model that integrates the microscopic-level processes (the nanobiology) into a cell- or tissue-level description. Significant progress on the development of computational algorithms for a whole-cell model has been made, and the proposed work is aimed at the development of a new microscopic model of force generation in a cell, and the integration of the microscopic model into a multicomponent 3D continuum description based on spatially- and temporally-varying material properties. A significant product of the research will be a computational tool built around modular descriptions for signal transduction, force generation, and movement that can be used to test new hypotheses and to do experiments computationally that are difficult to do in the laboratory.