Cell crawling behavior is essential for human development, maintenance and defense, and instrumental in disease processes such as inflammation and the spread of cancer cells. This proposal addresses the machinery used by human white blood cells, tissue defense cells, tumor cells and blood platelets to crawl and change shape respectively. It focusses on two general questions based on key cell protein components which control how the major cell protein, actin, forms struts and levers that control cell shape and movements. These actin-regulating components were isolated originally from lung defense cells, the alveolar macrophages, and are believed important for lung protection and disease. The characterization of these proteins led to principles believed to explain how actin architecture, the so-called actin cytoskeleton, is maintained in the cell and how this architecture is changed to accommodate crawling movements. The current proposal sets out to explain how one of the components, a protein called filamin-1 , causes actin filaments to take on particular configurations within the cell and how signaling processes that mediate instructions delivered from outside cells to elicit crawling behavior might regulate filamin-l's functions, which also include linking the actin cytoskeleton to plasma membrane receptors and serving as a scaffold for cellular trafficking and signaling reactions. The proposal also plans to examine how human blood neutrophils, the most rapidly crawling of our cells, determine where and when to assemble new actin filaments, based on hypotheses derived from a systematic study of the second component, a protein named gelsolin. The investigations involve elucidation of how signal intermediates such as GTPases and phospholipids work to promote actin polymerization. The eventual goal is to understand these processes sufficiently to modify them in hopes of mollifying inflammation and metastatic tumor spread.
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