Control of cell shape and motion is a key aspect of development, wound healing, tissue remodeling, immune response, and unfortunately, tumor invasion and metastasis. Thus, a better understanding of the mechanics of cells will have implications not only for ideas about cellular function, but also for approaches to the many problems of cellular dysfunction (e.g. cancer, maladaptive remodeling in heart failure, etc.) that are responsible for much of the medical burden borne by an aging US population. From a mechanical viewpoint, amoeboid cells are flexible, membrane-enclosed bags filled with cytoskeletal polymers and molecular motors. Collectively, these agents maintain cell shape, orchestrate cell movements, and produce active forces as required by circumstances. When cultured on flat surfaces, most cells spread to take on a pancake shape. Motion is then mediated by a thin lamellipodium at the leading edge via a cycle of protrusion, adhesion and traction that pulls forward posterior regions of the cell. It is the overall goal of this application to develop a better understanding of the dynamics underlying these events by constructing and testing quantitative models of cellular morphology, motion, and force production. The specific aims are: [unreadable] [unreadable] 1. To contruct two-dimensional computer models (i.e. transverse sections in length and height) of lamellae and of whole fibroblasts with a view toward exploring not only lamellipodial protrusion, but also such phenomena as blebbing, ruffling and surface waves. [unreadable] [unreadable] 2. To develop a continuum mechanics theory of free-boundary flows in the "shallow-water' approximation appropriate for the study of thin layers such as lamellae. This will be the foundation for a "two and a half"-dimensional computer code (x,y and height parameter) able to model cytoplasmic flows in spread cells. [unreadable] [unreadable] 3. To use this shallow-water computational tool to model whole cell migration on a surface. Emphasis will be put on the analysis of popular experimental systems of motility such as fish keratocytes or 3T3 fibroblasts. [unreadable] [unreadable] [unreadable]
NIH ExPorter
NIH ExPorter