Cell migration is central to many biological and pathological processes, including embryogenesis, the inflammatory response, tissue repair and regeneration, cancer, arthritis, atherosclerosis, and congenital brain defects. While understanding the molecular basis of cell migration could lead to the development of novel therapeutic strategies for various pathological processes, the study of migration is challenging, because it requires the integration of many different cellular processes, including the formation of protrusions and the formation and disassembly of adhesions that occur in spatially distinct locations. While considerable progress has been made in identifying regulatory pathways that mediate migration, the mechanisms by which they mediate the formation and breakdown of adhesions are now key issues that are only beginning to be addressed. Recent imaging technologies offer great promise for addressing adhesive mechanisms in migrating cells by providing quantitative assays for measuring the kinetics by which components locally enter and leave adhesions and spatial maps of adhesion molecule dynamics, including binding and flow kinetics, clustering, and interactions. In addition, new mass spectrometry methods are producing maps of utilized phosphorylation sites on proteins and thus, paving the way for identifying and studying key regulatory interactions. In this proposal, we will use these new imaging technologies and assays to determine the relative kinetics by which components enter and leave adhesions, elucidate the role of contractility and regulation of integrin-cytoskeletal linkages, characterize key sites of regulation in adhesion assembly and disassembly, and identify the mechanisms used to target components to adhesions in protrusions. We will study neuronal and fibroblastic cells using a prioritized list of signaling and structural molecules. In addition, we will translate this research on dissociated cells migrating in culture to migration of neuronal cells in vivo and to the dynamics of dendritic spines on neurons, which share molecules and analogous processes. The proposed studies bear directly on mental retardation and Huntington's disease. ? ? ?
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