Project abstract for group othmerhg

Computational Studies in Cell Motility

Cell locomotion plays an essential role during embryonic development, angiogenesis, tissue regeneration, the immune response, and wound healing in multicellular organisms. Movement is a very complex process that involves the spatial and temporal control and integration of a number of sub-processes, including the transduction of chemical or mechanical signals from the environment, intracellular biochemical responses, and translation of the intra- and extracellular signals into a mechanical response. While many single-celled organisms use flagella or cilia to swim, there are two basic modes of movement used by eukaryotic cells that lack such structures - mesenchymal and amoeboid. The former, which can be characterized as "crawling" in fibroblasts or "gliding" in keratocytes, involves the extension of finger-like pseudopodia and/or broad flat lamellipodia, whose protrusion is driven by actin polymerization at the leading edge. In the amoeboid mode, which does not rely on strong adhesion, cells are more rounded and employ shape changes to move - in effect "jostling through the crowd" or "swimming." Here force generation relies more heavily on actin bundles and on the control of myosin contractility. Leukocytes use this mode for movement through the extracellular matrix when adhesion molecules have been knocked out. However, recent experiments have shown that numerous cell types display enormous plasticity in locomotion, in that they sense the mechanical properties of their environment and adjust the balance between the modes. Thus pure crawling and pure swimming are the extremes on a continuum of locomotion strategies, but many cells can sense their environment and use the most efficient strategy in a given context.

One objective of this research is to understand how shape changes can propel cells, the forces that drive the shape changes, and what determines the efficiency of a stroke. Another objective is to understand the cytoskeletal changes needed to produce the shape changes, beginning with blebbing. Blebs result from actomyosin contractions of the cortex, which cause either transient detachments or local rupturing of the cortex. While much less studied than actin-driven extensions, blebs are used as an alternate mechanism for movement by many cell types, and also play a role during cytokinesis and apoptosis.

Another major aspect of this research concerns the signaling networks that control the dynamic rearrangements of the actin cytoskeleton. The pathways involve Rho GTPases that act as molecular switches that relay extracellular signals, both receptor-mediated signals and mechanical signals transduced via integrin-mediated adhesion to the extracellular matrix. Recent experimental work has shed light on the networks involved, but a synthesis of these results into an integrated model that can predict how the balances between the pathways determine whether the amoeboid or mesenchymal mode prevails is needed.

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