The proposed Program Project focuses on the structure and function of the beta3 integrins, alpha-IIb-beta3 and alpha-v-beta3.The target cells for study will be platelets and endothelial cells. Analyses will be performed to understand the molecular mechanisms, which regulate the contribution of alpha-IIb-beta3 and alpha-v-beta3 to the adhesive and migratory responses of these cells. The information derived from these studies will, in turn, provide insights into the complex biological responses of these cells, including platelet aggregation and the angiogenic response of endothelial cells. The Program will consist of four projects, each directed by an independent faculty member at the Cleveland Clinic. Dr. Edward Plow, Ph.D., will serve as Program Director and lead Project 1. This project deals with the molecular basis for alpha-IIb-beta3 activation and ligand binding. The theme of integrin activation will be continued in Project 2; Dr. Jun Qin will use multi-dimensional NMR to examine how talin interacts with the beta3 cytoplasmic domain to induce integrin activation and how the conformation of talin regulates this interaction. In Project 3, Dr. Joan Fox will analyze the sequential assembly of signaling and cytoskeletal proteins at the cytoplasmic face of beta3 integrins during signaling events. The mechanisms by which the angiogenic growth factor receptors of the VEGFR family modulate the activation state of alpha-v-beta3 to influence angiogenesis and lymphangiogenesis will be investigated by Dr. Tatiana Byzova in vitro and in vivo in Project 4. Three Cores (an Administrative, an Expression and a Cell Culture and Isolation Core) provide infrastructure support. A theme which transcends all four projects is the bi-directional signaling across the beta3 integrins: inside-out signaling events that lead to activation of both alpha-IIb- beta3 and alpha-v-beta3 and the outside-in signaling events that are induced by ligand binding and lead to tyrosine phosphorylations, cytoskeletal rearrangements and formation of focal complexes and subsequent down-stream responses. The approaches to be taken will include analyses of transgenic animals, multi-dimensional NMR, in situ microscopic image analyses and sophisticated protein chemistry, mutational and functional studies. Overall, the proposed Program combines the senior leadership of Drs. Plow and Fox, who will each be relinquishing an existing grant to continue their projects in the context of the Program Project, with the state-of-the-art approaches applied by Drs. Qin and Byzova. Cementing the Program together is the cohesive focus on the beta3 integrins; multiple collaborative interactions among the projects; and a common objective of the Program investigators to bring new insights into the structural and biological mechanisms that regulate the function of the beta3 integrins.
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