Macrophage /monocyte signaling in vascular pathophysiology

$439,383P01FY2002HLNIH

University Of Connecticut Sch Of Med/Dnt, Farmington CT

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Abstract

Monocytes and macrophages play important roles in chronic inflammatory reactions that occur in a number of pathophysiological processes, including atherosclerosis, adult angiogenesis, rheumatoid arthritis, inflammatory skin conditions, and allergic reactions, etc. These cells are regulated by chemoattractants, including chemokines. Chemoattractants elicit various cellular responses in monocytes and macrophages through their cell surface receptors and intracellular signaling intermediates, which form the signal transduction pathways. In this proposal, we propose to investigate two important chemoattractant- regulated signaling pathways: one mediated by phosphatidylinositol 3- kinase (PI3K) gamma and the other by phospholipase C (PLC) beta 2 and beta 3. We plan to determine the precise roles that these two signaling pathways have in the regulation of various monocyte and macrophage responses to chemoattractants and in two vascular remodeling paradigms atherosclerosis and angiogenesis in which the monocytic cells are critically involved. Specifically, we will 1) Characterize in vitro the roles of PLC beta2/3 and PI3Kgamma- mediated signaling pathways in chemoattractant induced responses, including chemotaxis, superoxide production, adhesion, differentiation from monocyte to macrophage and apoptosis, using macrophages and monocytes isolated from the wildtype and mutant mice. This study will facilitate the understanding and implementation of the in vivo studies. 2) Investigate the role of PI3Kgamma and PLC beta2/3-mediated signaling in angiogenesis using the Matrigel angiogenesis model. 3) Investigate the role of PI3Kgamma and PLC beta2/3-mediated signaling in atherosclerosis by generating and studying mouse models. This work is anticipated to provide insights into the role of monocytic cells and their signaling events in pathogenesis of inflammation-related human diseases and may reveal potential targets agents for treatment of these diseases. These studies have relevance to pathologic vascular remodeling events, in which the normal vascular tree develops into pathologic plaques.

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