The central objective of Project 1 is to define the properties of the novel, oxidant-sensitive transient receptor potenfial melastafin (TRPM)2, a Ca(2+)-permeable channel in lung endothelial cells (ECs), how it regulates Ca(2+) signaling, and its role in the mechanism of neutrophil-dependent increases in lung vascular permeability and infiammatory injury. Our approach will be to identify the essenfial role of neutrophil-EC interactions in activafing the TRPM2 channel, then its mechanism of activation, and finally define how TRPM2 activation leads to increased lung endothelial permeability and transmigration of PMNs at the level of adherens juncfions.
Aim #1 will test the hypothesis that PMN interaction with the lung endothelium via beta2-integrin/ICAM-1 binding increases lung vascular permeability through the activation of TRPM2 channels in ECs.
Aim #2 will define the role of the short splice variant of TRPM2, TRPM2-S. in regulafing TRPM2-mediated Ca2+ entry in lung ECs and in the mechanism of endothelial hyper-permeability and PMN transmigration.
Aim #3 will determine the role of NF-kappaB-dependent ICAM-1 expression in amplifying TRPM2 acfivity in ECs and thereby in mediating PMN-dependent lung infiammatory injury. The proposed studies will use molecular, genefic. and physiological approaches in EC monolayers co-cultured with PMNs and mouse lung models (including the recentiy developed TRPM2(-/-) mice). These data will provide new insights into the mechanisms of acute lung injury and specifically theTRPM2-activated pathways that mediate lung injury. Furthermore, we believe that it will be possible, with a new understanding of this transcellular cross-talk, to block inappropriate neutrophil-EC interacfions and PMN-mediated lung injury by interfering with TRPM2-activated signaling pathways.
Project 1 of this Program seeks to define the properties of a calcium-permeable plasma membrane channel on lung endothelial cells that is acfivated by the interaction of endothelial cells with activated circulating neutrophils. We will study the role that this interacfion and channel acfivafion has on inflammatory injury in the lung vasculature and identify potential therapeutic targets in the signaling pathways.
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