Indentification of novel molecular components at the cell periphery: taking advantage of EPEC pedestals

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The sub-cellular molecular events that occur at the cell periphery are crucial for organ development, maintaining cells and tissues, and healing. Aberrations to the "normal" functions of proteins within cells often lead to the manifestation of diseases. The cellular skeleton (the cytoskeleton) is a dynamic grouping of filamentous protein-based structures. In the majority of cells, the most prominently studied of these components are the actin filaments. These filaments are key sub-cellular elements involved in whole cell movement, transport of particles within cells, and the internalization of molecules from outside of the cell to the cell interior. During bacterial interactions with cells, these organisms often commandeer the cells for their own purposes. One of these bacteria, enteropathogenic E.coli (EPEC), remain outside of the host cells and inject bacterial proteins to control the host cell's functions. These bacteria continuously interact with the cell periphery and generate actin-rich structures (called "pedestals") at the bacteria/host cell contact points. Proteins identified at these sites are essential factors for normal cellular functions. In order to identify new proteins at the cell periphery, we will examine EPEC generated pedestals and exploit them as a model system. As pedestals are of uniform length and are relatively large, we will use advanced cell biological techniques to identify and functionally determine proteins in these structures. Newly identified proteins will be extensively characterized at pedestals and the cell periphery in motile as well as immotile cells. Through understanding the molecular components at the cell periphery, the work outlined in this proposal will generate profound insight into normal cellular physiology and will provide targets to examine during various diseases.