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 focuses on a key cell protein component, filamin A, which controls how the major cell protein, actin, forms struts and levers that regulate cell shape and movements. Filamin A was isolated originally from lung defense cells, alveolar macrophages, and is believed important for lung protection and disease. The characterization of filamin A led to principles that 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 is to explore how filamin A 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 regulate filamin-A'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 eventual goal is to understand the structure and regulation of filamin A sufficiently to modify them in hopes of mollifying inflammation and usefully impacting on what we believe are many aspects of human physiology controlled by filamin A.
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